CA2544808A1 - Inotropic orthorythmic cardiac stimulator - Google Patents

Abstract

Automatic, programmable and implantable cardiac pacing device (STIO) allowing a control of the c.oelig.ur, accompanied by a strong increased contractility of myocardial cells with each beat caused by an optimized post-extrasystolic strengthening effect. The STIO does not cause lasting fatigue to the myocardium, it increases strongly, instantaneously and sustainably the coronary flow, makes the dilations of the walls, opposes thromboses, arrhythmias. STIO creates a genetic involution of the pathological process either by the sole effect of the mechanosensitivity of certain genetic expressions, either by adding partial autologous cell dedifferentiation, obtained by original genetic manipulation, inducing physiological regeneration and anatomical. This method also makes it possible to create arterial stents physiological and auto-contractile, including coronary, as well as transplantation of dedifferentiated myocardial cells.

Description

ORTHORYTHMIC CARDIAC STIMULATOR INOTROPE.
The subject of the invention is an electrical stimulation device for the heart allowing, in particular, to improve hemodynamic performance, those of the heart cells and in particular the blood flow, and this especially in patients with heart failure, or tachycardia or arrhythmia, including severe heart failure or acute, left or right, systolic or diastolic or global.
The subject of the invention is also a method of piloting such device.
The subject of the invention is also a method of electrical stimulation of the heart as well as the cellular improvement of the heart implementing such device, particularly in the patient suffering from heart failure, or tachycardia or arrhythmia, including heart failure acute, left, right, or global.
Until now, the devices for automatic stimulation of the heart, also called pacemakers, are intended primarily to replace or regulate the spontaneous electrogenesis of cardiac muscle activation.
An important step has been taken for the control and reduction of tachycardias, tachyarrhythmias or extrasystoles isolated in the processes and devices described in Zacouto patents US-A-4,052,991 and US Patent 3,857,399. These improvements made it possible, in particular, change the coupling intervals of electrical stimulation based of the variable duration of the previous cycle (s), for example according to a percentage of this duration. These improvements allowed, moreover, to send stimulations in salutes and ramps. They also allowed differential markings of local detection and stimulation spots on the electrocardiogram.
Paired (STP) or coupled stimulation (STC) and optimal inotropic stimulation (STIO) tries to manually or automatically periodic succession of inhibitions and myocardial stimulations with preferably, parameters for obtaining a hemodynamic maximum and anti-arrhythmic protection. The STIO allows, in principle, stronger mobilization of energy reserves and acquisitions myocardium, which is generally all the greater because it is more

2 tired (Wayne Cooper: Postextrasystolic Potentiation, Circulation, Theft No. 6, 2962, Dec 1993) such as, for example, increased activation a pentose cycle in addition to the Krebs cycle (hexoses) and / or activation enhanced and resynchronized some ion channels and electrons transmembrane effects, the increase in concentrations and intra-calcium ion cells, secretions of vaso- or myoactive peptides and modifications of certain expressions, translations and transductions local genetic adaptations to a biochemical myocardial energy reinforced type "sports heart". This instantaneous reinforcement, important and lasting, with no known limit in time, of contractility after certain extrasystoles is well known to cardiologists as reinforcement post-extrasystolic (EPR). EPR (or PESP) is a natural phenomenon which demonstrates the possibility of further mobilizing acquisition and the expenditure of the myocardial energy reserves, which remain often inhibited during its failures (other than certain tachycardias ectopic). Persistence of EPR even in acute severe failure myocardium (example: pulmonary edema after recent anterior infarction extended myocardium) or chronic (Classificat., New York Heart Assoc., classes 2 to 4) shows the possibility of using the ~ STP in these cases clinics.
However, the paired stimulation (STP) published in particular since 1964, widely tested in animals and in several trials clinics to reduce or better withstand certain tachycardias and myocardial failures (for example, F. Zacouto et al., Paris, Nouv.
Press Med. 1974, 3, No. 22, p. 1448), is hardly ever used in cardiology. This is explained by the use of stimulation and heart detection tragically inadequate as unable to continuously target the narrow and often unstable critical areas in each cardiac cycle (CC) which is nevertheless essential to reach for

3 o achieve an optimal, continuous, oxygen-efficient and anti-arrhythmic.
In general, the devices currently in use do not not allow, through electrical stimulation, to sustainably improve the hemodynamic performance of the heart muscle, especially in patients where this performance is significantly reduced, in particular in patients with severe heart failure.
Since the nineteenth century, the phenomenon of strengthening post-extrasystolic contraction (Post-extrasystololic PESP Potentiation in English).
Thus, the applicant was able to obtain, in two patients insufficient Acute left ventricular, a temporary improvement of hemodynamics by pairing, after a manual start adjustment, a paired stimulation including bursts of stimulation pulses 1 o consecutive consecutive in the same coupled cardiac cycle, on the wave R, towards the end of the refractory zone (F Zacouto et al., Paris, New Press Med., 1974, 3, No. 22, p.1448).
Major research was then conducted on the phenomenon of post-extrasystolic reinforcement in order to try to enjoy the improvement of the mechanical contraction triggered by the sending electrical stimulations provoking a stimulated extrasystole (see, for example, for example, US 3,939,844 and US 5,213,098). However, despite important work over a long period, the researchers are finally come to the conclusion that the problem of establishing, in a way lasting and effective, a strengthening of myocardial contractility by the paired stimulation, could not be solved, and despite the promises of this In principle, the results of the studies have been discouraging (see for example N. Wayne Cooper, Post-extrasystolic Potentiation, Circulation, Vol 88, No. 6, 2962, Dec. 1993).
These failures can be explained, in particular, by the fact that electrical refractory ZRE and myocardial ZRM and the corresponding metabolic reactions can vary significantly at each cycle, especially in the event of myocardial irregular rhythm.
More recently, proposals have been made to create devices capable of addressing the heart of paired or coupled bursts impulses intended either to provoke, according to one hypothesis, an action of myocardial sensitization during the electrical refractory period, ie at generate, shortly after the end of the electrical refractory period, a electrosystem intended to induce post-extrasystolic reinforcement during

4 of a posterior systole. Different documents deal with the research of this reinforcement such as WO 02/53026 and WO 03/20364.
However, this research is hampered by the fact that stimulation paired or coupled is not compatible with the presence, frequent especially in patients with heart failure, arrhythmias or tachyarrhythmias, when she does not provoke them herself on already unstable hearts.
The present invention proposes, and this against the difficulties and discouraging conclusions of the research, to provide a device and processes allowing a lasting and significant improvement of the hemodynamic performance of the heart by electrical stimulation.
Another object of the invention is to treat arrhythmias or tachycardias, including recurrent or non-fast tachycardias reducible by antitachycardic pacemakers (Zacouto, US-3,857,399 and US-4,052,991), including in patients with heart failure and to improve instantly hemodynamics, whether the tachycardia is reduced or not.
In its general framework, the invention proposes to improve a device for stimulating the heart muscle allowing an increase significant hemodynamic performance of the heart and / or treatment tachycardias comprising a device preferably permanently implanted 2 0 including means for automatic acquisition of the heart rhythm, particular to know the interval between at least the two last R waves (induced or spontaneous) of the cardiac cycle that comes to end, - means for determining, preferably in real time, the duration of the electric refractory period (ZRE) following the last wave R
of that cycle, - and means to address, substantially without delay to or to the end of said refractory period (ZRE), at least one pulse of stimulation.
3 o The coupling stimulation pulse or that of the pulses of the salve that stimulates the heart generates a wave (R ') causing no reaction mechanical, but causing an additional electrical refractory area ZR, contributing to the desired inotropic and anti-arrhythmic effect.

An object of the invention is a stimulation device and / or strengthening of the heart muscle and / or myocardial cells allowing a significant increase in hemodynamic performance heart and / or treatment of tachycardias, tachyarrhythmias or fibrillations

5 ear, including means for automatic acquisition of the heart rhythm, and optionally from its origin, allowing in particular to know the interval between at least the last two R waves (caused or spontaneous) of the cardiac cycle that has just ended, means for precise acquisition of cardiac hemodynamics, means for determining, continuously in real time the duration of the electric refractory period (ZRE) following the last wave R
of that cycle, means for evaluating at least one parameter relating to the cellular functional state of the myocardium, and means subordinate to said evaluation means for address substantially without delay at the end of the said refractory period (ZRE), at least one stimulation pulse, paired or coupled, adapted to said state cellular functional.
In a particularly preferred manner, said evaluation means determine an effective critical area to target ZCE, which is immediately after the end of the electric refractory zone, and ends at the end of a refractory zone of maximum myocardial contraction ZRMM, sending said stimulation pulse intervening in said zone ZCE, if it is present and targetable, and does not cause intractable arrhythmia. In the latter case, means to automatically reverse, for example, 20 ms in 20 ms, the zone ZCE are planned, while monitoring hemodynamics and metabolic consumption of myocardium.
Preferably, said evaluation means try to detect or 3 o check at each cycle the threshold of excitability of the myocardium.
Preferably, according to the invention, the device is arranged to determine at each cycle, and preferably in real time, the duration of said electric refractory period (ZRE).
Advantageously, the determination of the refractory zone occurs in a part of the heart in which the impulse or burst of

6 stimulation is addressed, for example using the same electrodes for detection and stimulation, or very close electrodes.
In an advantageous embodiment, it is by the end of the said refractory period (ZRE), a burst of pulses of stimulation, the duration of the salvo and the repetition interval of pulses being such that a burst stimulating pulse is found addressed to the heart substantially without delay after the end of the said period refractory.
Preferably, the stimulating pulse sent to or at the end of the refractory period is addressed, almost without delay, for example between 10 and ms after the end of the ZRE refractory zone. In the case of a salvo, it is however necessary that the beginning of the salvo occurs inside and towards the end of the refractory period.
It can be seen that one can thus obtain, by a simple device Implanted, enhanced contractility and generated hemodynamics by at least one of the pulses for stimulating the burst, in particular case of acute or severe heart failure.
At the same time, we obtain on tachycardic hearts a decrease important permanent ventricular rhythm and a strengthening of the 20 contractility of the heart.
It results, in particular, that one obtains cardiac contractions significantly more efficient and this without causing a excess oxygen consumption of the heart intolerable because the increase in oxygen consumption is offset by the increase concomitant coronary flow and overcompensated by the gain of the contractility.
The device is thus able to perform paired stimulation or optimized inotropic coupling, hereinafter referred to as STIO.
The determination of the duration of the refractory zone ZRE of the cycle in course can be conducted from characteristics of the previous cycle, or even from previous cycles. For example, it can be assessed a priori as a percentage of the duration of the previous cycle, this percentage increasing if the cycle time decreases. For example, the percentage will be 25 to 30% for a rate of 60 p / min and 50 to 80% for a rate of 120 p / min.

7 The evaluation of the duration of the refractory zone may be carried out by any other means already known to cardiologists, for example by scanning of an electrical pulse in a delayed burst, cycle in cycle until the acquisition of a generated electrosystem. The duration ZRE
obtained can then be used during one or the following cycles for sending the pulse or bursts of stimulation pulses.
In the case where, instead of a burst, the device generates a single stimulation pulse, the means (4) for determining the duration of the refractory zone are arranged to acquire by a scan of a second 10 impulse, the substantially exact duration of the refractory zone, this sweep being conducted for example during previous cardiac cycles or in Classes.
When using a burst of stimulation pulses, this one will begin, preferably, a little before the estimated end of the refractory period ZRE and the duration of this salvo and, therefore, the number of pulses of stimulation will be advantageously such that a stimulation pulse can intervene very quickly after the end of the said refractory period.
These means of determining the duration of a refractory zone of the heart are known cardiologists.
In a variant of the invention, in the case where the stimulation at the end of the refractory period ZRE is effected by sending a burst of pulses, the device can send the salvo substantially before the estimated end of the refractory period ZRE, and detect without delay, in the same cycle, preferably at the same location of the heart, which impulses the burst causes an electrosystole R ', for a given stimulating amplitude, which provides the ZRE duration that has just passed. This duration detected allows, in addition, to determine the probable duration of the ZRE refractory zone next cycle.
Preferably, anti-stimulation means are provided.
3 o tachycardia and means sensitive to extrasystoles to stop automatically said stimulation in case of occurrence of instability excessive hemodynamics or electrical arrhythmia responding to predetermined criteria.
In an improved embodiment, one can refine the determination of the ZRE refractory zone of the next cycle taking into account

8 one or more parameters detected and this taking into account the stability functional and rhythmic heart.
These parameters may include - duration of previous or current cycles, - hemodynamic parameters, metabolic consumption and threshold of excitability during a number of consecutive contractions comparable, compared with thresholds.
In case of significant discrepancy between, for example, the ZRE zone calculated using the ratios between QT intervals and intervals RR
1o real patient, as is known in cardiology, and ZRE area measured, the myocardium may undergo a metabolic change that may be precede a serious arrhythmia if the ERZ decreases, a recovery functional if the ERZ extends.
The device monitors and differentiates these two cases and reacts instantly according to a schedule. For example, in case of arrhythmia severe, it stops the stimulation or modifies the stimulation parameters.
It can be expected that the burst of stimulation pulses can be advanced or retracted from an estimate of the refractory zone, and / or the interval between the pulses in the burst and / or the amplitude of the pulses decreased or increased, the device having acquisition means automatically, in particular by obtaining the intracardiac ECG allowing to determine what is the stimulus pulse in the salvo that has triggered the wave R ', and, consequently, possibly modify the burst.
Such a device will be particularly indicated for reducing the tachycardias, including sinus tachycardias of the insufficient heart.
Preferably, the device comprises means sensitive to the waves R spontaneous or stimulated and / or determination of refractory areas electrical and mechanical equipment, in particular by scanning the entire salvo or only within this salvo and / or means of determination without delay the thresholds of excitability of the heart, for example by providing for stimulation pulses of varying intensity, including subthreshold for allow their measurement. It is also planned to be able to control the pacemaker as a conventional anti-rheumatic stimulator tachycardic and reacting to extrasystoles and being able to stop

9 automatically the STIO programmed in case of occurrence of instability hemodynamic too big. In case of excessive instability of the zones refractories or thresholds of excitability of the myocardium or both at the same time, one can, for example, increase the durations and / or the number and / or the voltage of the burst pulses or program the stop of the operating from a threshold.
Preferably, the device is characterized in that it comprises, in in addition, means of very precise acquisition of cardiac hemodynamics.
These means are, in themselves, known and preferably comprise one or intracardiac pressure sensors or such sensors arranged to proximity. Preferably, sensors for determining variations cardiac volume, for example impedance proximity sensors known electrical devices, including juxta- and intracardiac, are also used to acquire the precise pressure / volume curves of the contraction heart.
In an improved embodiment of the invention, a device according to the invention, implantable or even external non-implantable, can include, besides the means of acquisition of rhythm, the means of determining refractory zone duration and the means for sending a impulse or salvo, as described above, means sensitive to accurate acquisition of hemodynamics to determine variations effectiveness of the hemodynamics, these means being capable of order the sending and possibly the parameters of the impulse or the salve and / or the application of a dose of external infused drug or from an implanted drug reservoir until a degree of hemodynamic performance, for example programmed or determined in advance, or in a manner close to that which produced the most favorable hemodynamics for the patient at a given time.
Various aspects of the invention will now be described.
STIO control In general, and particularly in severe deficiencies or acute, present variations of electrical refractory zones (ERZs), mechanical refractory zones (ZRM), thresholds of excitability, haemo-dynamics and metabolic behaviors can not, to them only predict the evolution of the intramyocardial functional state of the coupling Electromechanical (EMC). This one (CEM) is observable only by the specific, precise and individualized temporal comparisons that can be give the device according to the invention, in particular in the form of a simulator 5 analyzer (SIMA), without which the fast myocardial failures can remain unpredictable and unstoppable by the STIO.
Optimum and continuous maintenance of the STIO parameters in relation to variations in myocardial excitability thresholds In a preferred form of the invention, a monitoring is carried out continues the threshold of excitability of the heart by means of a periodic decrease stimulating energy used in accordance with the Zacouto patent FR-A1-1,237,702, PV 651,632 of July 11, 1953 and allowing a readjustment instantaneous stimulation parameters. One way to achieve this can to gradually or suddenly reduce the stimulating impulse from the train of pulses until recapture of this pulse. During the periods when this pulse remains ineffective, the impulse that follows in its train takes control of the heart. When a decrease in energy stimulant remains sufficiently reliable, the STIO can be programmed to 2 o initiate a stimulation, for example, with a decreased amplitude, which also decreases the risk of causing extrasystoles. We can also, for example, reduce by one third the amplitude close to the threshold of three or first four pulses of a train with six or eight pulses for observe whether this targeted stimulation sub-threshold or not promotes the threshold ' of myocardial excitability. If this threshold is reduced, we can quantify this "facilitation", for example, as a percentage of decreasing amplitude and, by repeating this examination periodically, measure its duration of facilitation.
Conversely, a stall of the stimulating impulse or the entire train of stimulation will trigger an instantaneous rise in amplitude energy of the impulse become infra-liminary or the whole train stimulant of the next cardiac cycle. For the following cardiac cycles, it is advantageous to use a voltage pulse ramp gradually increasing to determine, by automatic measurement at inside each cardiac cycle, for the software program Inotropic orthorhythmic therapy, the new threshold of myocardial excitability from which a new process of control and intervention on the amplitude of the stimulating pulses will start.
Thus, the STIO realizes an optimal permanent instant adaptation stimulating intensities according to their coupling intervals with respect to the previous R wave, whether it be a decrease or a decrease spontaneous increase in myocardial excitability thresholds.
When seeking to specify a threshold of myocardial excitability, realizes that it is not a point limit but an area between the sub-liminary amplitude where we do not observe any stimulation propagated, and the supra-liminal amplitude where we observe a training constant spread. The extent of this area of inconstant excitability is variable.
In a particularly preferred manner, the device comprises means to give a pulse intended for electrical stimulation, a amplitude greater than 30%, and preferably between 30% and 90%
the amplitude of the last sub-threshold pulse found.
The parameters on which the device acts can be simply a programmed ventricular rhythm and / or automatic adjustment of the beginning or the end or duration of the salvo or the number or characteristics (including width, polarity, intensity) pulses in the burst, or still a location of sending the salvo on different electrodes of stimulation. For example, one can gradually reduce a salvo to a only impulse. For this, one can feel periodically with, at least, a second pulse that moves progressively from, for example, 25 ms ahead of the stimulating pulse and then step back step by step, for example 4 m / s at each cycle, to automatically measure the beginning of the zone non-refractory. When the exploratory pulse goes back to the impulse stimulating, this impulse is pushed back until it reaches the onset of decline in the ventricular pressure / volume curve or 3 o increase in oxygen consumption or secretion and membrane accumulation of electrons or, for example, catecholamines proximal or lactic acid, this position corresponding to the overrun of the end of the mechanical refractory zone with maximum active contraction said ZRMM.

Preferably, anti-stimulation means are provided.
tachycardia and means sensitive to extrasystoles to stop automatically said stimulation in case of occurrence of instability excessive hemodynamics or electrical arrhythmia responding to predetermined criteria.
The electrical stimulation of the heart according to the invention makes it possible to obtain each cardiac cycle (CC), paired (STP) or coupled (STC) stimulation optimum inotropic (STIO) by very precise adjustments of the pulses by electric refractory functional areas (ERZ) and myocardial disease (ZRM) and its corresponding metabolic reactions and in the space compared to the cardiac locations of the electrodes allowing to obtain the best hemodynamics, or antiarrhythmic efficacy.
These functional areas can vary significantly with each cycle, especially in case of myocardial pain. To control at each cycle the ZRE and ZRM and the corresponding hemodynamics, one can continuously analyze these areas in real time, for example through means described in Zacouto US Patent No. 4,052,991 and 3,857,399.
The device may include means for reducing gradually a salvo to a single or a small number of pulses, in particular by periodically testing with, at least, a second impulse that moves progressively ahead of the stimulating impulse for automatic measuring the beginning of the non-refractory area, so that, when the exploratory pulse goes back to the stimulating impulse, this may be retreated, in particular periodically in case of instability of the operation until obtentà © loon the beginning of decline of the curve ventricular pressure / volume or increased consumption of oxygen or a corresponding parameter, in particular the secretion membrane of electrons, local pH or ketone bodies, this position corresponding to the exceeding of the end of the mechanical refractory zone at 3o maximum contraction (ZRMM).
It may include means to switch from paired stimulation to coupled stimulation, i.e. at a fully stimulated rate means being sensitive to the means for acquiring the electrocardiogram and / or hemodynamics, and / or myocardial metabolism.

Instantaneous inhibition of extrasystoles or arrhythmias during STIO
The device according to the invention can also be arranged to treat the extrasystoles and arrhythmias that may appear, either spontaneously, either under the effect of the operation of the device.
A condition for the proper functioning of the STIO is to instantly detect early extrasystoles that may follow or accompany a train of impulse and react also instantly in causing stimulation or a train of stimulation from the beginning of the detection of such an extrasystole. Instant detection of a extrasystole Early warning requires ECG recording, preferably independent of its intramyocardial directional spread that is slow (1 mlsec) before to arrive at the intracardiac detecting electrode. For this, we can use a detection by juxta- or extracardiac or intracavitary electrodes ventricular, preferably without contact with the myocardium, which are sensitive to the speed of propagation of the variations of the electric field of the heart that is close to the speed of light.
As soon as the confirmed detection of a premature extrasystole is confirmed, the anti-arrhythmic program will instantly trigger a stimulation of burst preference from all stimulating electrodes available 2 0 in order to immediately provoke a fusion complex between the propagations of the stimulated and extrasystolic depolarizations. This fusion complex will block the spread of extrasystolic depolarization and will allow often the suppression of premature myocardial ectopias. We can also, when early myocardial ectopias mostly repeated threaten the effectiveness of the STIO, instantly shorten and temporarily diastoles to close non-refractory intervals of cardiac cycles during which the priming of early extrasystoles can intervene.
In such an embodiment, making it possible to treat the 3 o Arrhythmias and isolated extrasystoles, the device according to the invention can comprise a plurality of electrodes arranged in different locations heart muscle and / or distance from the heart and acquisition means sensitive to the electrical signals appearing on the electrodes and to distance from them to find, at an early stage, the occurrence of a electrical extrasystole in a myocardial zone close to those of electrodes initially concerned. The means of addressing the stimulation pulses are then made sensitive to such a finding to instantly emit into a nearby electrode or into a plurality of electrodes, an impulse or a stimulus burst whose electrical propagation in the myocardium goes to the myocardial zone affected by the extrasystole, and result in a fusion complex between them who can block the spread of extrasystole.
In order to detect early enough, and above all to be able to detect immediately send a stimulation pulse near the territory being affected by extrasystolic depolarization, the device is, preferably connected to a plurality of electrodes, such as electrodes at coronary sinus level, septum electrodes and free walls ventricular, and preferably juxtacardial, extracardiac or intracavitary electrodes, the device being arranged so that the means of acquisition detect the electrode near which the extrasystole is native, the means for sending a stimulation pulse or a burst being arranged to address stimulation at least from an electrode remote from the origin of the extrasystole.
So, when the STIO is disturbed by untimely occurrences extrasystoles apparently provoked by themselves, their suppression is favored by an instantaneous electrical response capable of occupying at earlier still non-refractory zones of a myocardium. To this end, it is better to detect extrasystoles not at the level of catheters bipolar intracardiac but at the extra-cardiac level. Indeed, the intracardiac detection does not "see" the extrasystole with delay corresponding to its speed of propagation from birth to the arrival under the sensing electrode that unfolds with a speed intra-myocardial of the order of 1 m / second. On the other hand, one electrode more external to the heart "sees" the myocardial depolarization spread with 3o a speed close to that of light. It is therefore necessary to detect the extrasystoles, and especially those considered by programming as dangerous, using juxta- or extracardiac electrodes; from the appearance of such detection confirmed as critical, it is appropriate to provoke a salvo of stimulation at one or more or preferably all stimulating electrodes. If you have multiple electrodes stimulating, it is necessary to stimulate them simultaneously from to cause fused QRS complexes that block spaces myocardial non-refractory thus preventing a spread of new premature. This system should act preferably within a single cycle 5 mechanical heart.
Sequential recording of extrasystolic events, particularly dangerous, allows the creation of registers in accordance with Zacouto US Patent No. 5,306,293; this opens the possibility, in case of recurrence of crisis, to exercise preventive 1o temporary acceleration of the basic rhythm before the new occurrence of these premature.
In another embodiment, in which the device includes means to quickly detect an extrasystole, 15 means of the device are sensitive to the acquisition of this extrasystole for reduce or even eliminate, preferably temporarily, the phases diastolic electric (D). This is done either ~ by increasing the rate of stimulation in a heart under electrical control of the device, either in taking control to address a pacing pulse, at the very beginning 2 o electrical diastole.
In these latter cases, the device according to the invention moves from the state of paired stimulation in the coupled stimulation state.
This can prevent the installation of a tachycardia while now at a much lower rate than the first tachycardic rhythm, 25 and benefiting from a post-extrasystolic strengthening effect.
Such a device is particularly effective for controlling nascent arrhythmias provoked by stimulation or of origin close to the or areas in which the pulses or bursts of stimulation.
In another embodiment, it can, in case of appearance arrhythmia, temporarily increase the number and / or intensity of impulses of the salvo to enhance the stabilizing effect on the myocardial cell membranes or administer automatically, by STIO program, a drug infusion or from a reservoir of implanted drug (see in particular Zacouto, US-A-5,305,745).
In other cases, the device can be arranged, in case of arrhythmia, to, on the contrary, decrease the intensity of the pulses of the salvo, the device monitoring then if the arrhythmia continues. In this case, the intensity of the stimulation can be increased.
In another embodiment, the device according to the invention can be used effectively in case of atrial fibrillation, resulting 1 o a ventricular arrhythmia. The device according to the invention is arranged for acquire the cardiac mechanogram, preferably until the occurrence of a cycle long enough to get a good myocardial contraction by momentary rhythm, defined, for example, by a predetermined threshold programmed and the stimulation means then send an impulse or a salve of stimulation at a moment located inside the systolic plateau of the mechanogram curve, that is to say from the top, relatively flattened mechanogram curve.
The device having acquired an immediately previous cycle, it is possible to locate the electric refractory period ZRE as a percentage of the duration of the 2o previous cycle, the pulse being launched in said plateau of the curve hemodynamic preferably a little before the end of this refractory zone maximum mechanical contracted, for example 30 to 40 ms before the end of this zone ZRMM, which end of zone can be detected by a intramyocardial microsensor of local pressure at the place close to The active electrode for sending a burst of pulses spaced 15 ms after which the device immediately stimulates, preferably multipolar, after the end of the electrical refractory zone that has just been prolonged, thus canceling the electric diastole. Advantageously, this can be performed on electrodes located near the area having 3 o have seen the arrhythmia using electrodes arranged as described above.
For example, the device may first stimulate the atrium, by a Intra-auricular electrode, then, if necessary, the ventricle by an electrode intraventricular, according to a well-known succession in the pacemakers of type DDD. We can thus, by STIO stimulation at the auricular level, regenerate or improve atrial myocardial tissue.
In another embodiment, when the bundle of His patient is more or less blocked, for example by Digoxin, one can gradually decrease the stimulation frequency by monitoring the premature contractions of atrial origin.
The device according to the invention can be integrated into a defibrillator (ICD), for example an implanted defibrillator, and be particularly after a shock of defibrillation, or even preventive of serious arrhythmias.
Implanted defibrillators currently include means antitachycardic, antiarrhythmic type according to US Patent 3,857,399 Zacouto, and the device according to the invention can, for example, be operated when the antitachycardia device fails to rapidly reduce tachycardia.
Inotropic stimulation during the muscular refractory zone of maximum contraction (ZRMM) In a preferred mode of optimization, the software controlling the device according to the invention is programmed to automatically find the narrow area effective ZRMM in each cycle concerned, and possibly, reduce then the different parameters of the pulse bursts, in particular their number, to achieve, if possible, a single pulse perfectly targeted. Since such stability of the operation of the STIO is non-existent or inconstant, especially in cases of myocardial programming that continuously detects mechanical parameters, preferably with their metabolic consumption (oxygen or equivalent), will have to reverse, in case of sufficient or increasing instability, the process of 3 o reduction of bursts to find without delay with bursts the location of the new useful narrow zone of the cycle. A quick method to find the ZRMM area is to detect, inside a salvo, the efficient pulse that produces a propagated depolarization and reduce progressively its distance from the impulse that precedes it until what she picks up and no longer causes visible electrogenesis on the electrocardiogram, which will be, at that moment, caused by the impulse next to the salvo. We thus know precisely the beginning of the useful zone and we can add about 20 ms, and consider that this interval represents the area useful for a given period. This period should be repeated periodically automatic search, very innocuous for the patient, so as not to lose the exact location of the ZRMM during its variations. Can also, after finding the effective pulse of the pulse burst, reduce the voltage or the width of other pulses so as to make them slightly infra-liminary, which may maintain their anti-arrhythmic effect and functional sentinel, because an infra-liminal pulse close to the threshold often influences this threshold by decreasing it for a short time (effect of facilitation). The automatic measure of this phenomenon can be done in slightly decreasing the intensity of the preceding impulse (s) the stimulating impulse in a salvo and gradually decreasing the intensity, voltage or width of the stimulating pulse to its functional stall, the next impulse of the salvo keeping an intensity stimulating; we can then gradually decrease the intensity of this impulse to measure the variation of its threshold of excitability and, in the progressively shifting in time, we can measure the duration and The intensity of this facilitation effect.
Alternatively, in order to detect the maximum contraction zone ZRMM, the device may comprise means for accurately measuring the volume of the heart or part of the heart by electrical impedance, or by localized ultrasound, for example by including an ultrasound probe Tissue measurement ultrasound, directed towards a cardiac wall for measure its displacement, allowing to obtain in real time the variations of myocardial volume, and thus determine the moment of contraction Max.
The subject of the invention is thus a device for stimulating and / or strengthening of the heart muscle and / or myocardial cells allowing a significant increase in hemodynamic performance heart and / or treatment of tachycardias, tachyarrhythmias or fibrillations ear, including means for precise acquisition of cardiac hemodynamics (5, 6) and including means for instantaneous detection of the refractory zone maximal myocardial ZRMM in a precise location of the myocardium, and means for addressing at least one stimulation pulse and, preferably, a burst of stimulation pulses from the region in which the occurrence of the ZRMM zone is detected.
It preferably comprises automatic acquisition means (1, 2, 3) heart rate and optionally its origin, allowing to know the interval between at least the last two waves 1o R (induced or spontaneous) of the cardiac cycle that has just ended, and means (4) for continuously determining in real time the duration of the electrical refractory period (ZRE) following the last wave (R) of a cardiac cycle, said device being arranged to detect whether a signal electrical depolarization has been produced by said stimulation in said zone ZRMM.
These means make it possible to detect and memorize the duration of said maximum myocardial refractory zone ZRMM and to address said impulse stimulation or burst of local stimulation pulses after a short duration after the start of the current cycle of the beginning of the ZRMM zone 2o and before the estimated end of said zone by storing said duration in previous cycles.
According to the invention, the pulse or at least one pulse of a stimulus burst, falls into said zone (ZRMM), substantially at the place of the myocardium where the occurrence of the zone (ZRMM) is detected.
The device may comprise pressure measuring means implanted intracavity and likely to detect a pressure zone maximum in the plateau of the cardiac mechanogram and to which are said means for sending a pulse or burst of stimulation.
Preferably, it comprises at least one detection sensor of intramyocardial pressure. Said intra-myocardial pressure sensor is located in the intra-auricular septum and / or in a free heart wall or intraventricular.
As a variant, it is possible to provide means for measuring the variation of volume of the heart or part of the heart, detecting and storing the interval of the cycle in which said volume has reached and maintains its minimum value, said means for addressing an impulse or stimulus burst being sensitive to said measuring means.
It is thus possible to provide means for detecting the consumption of the 5 oxygen core and / or equivalent, in particular local pH or concentration ketone bodies, and means for detecting the contraction zone maximum heart rate (ZRMM) by estimating by detecting, at one or several previous cycles, the relative position, in the cycle and / or in the mechanogram, the impulse or impulse of a salvo that has generated a

Post-extrasystolic reinforcement (PEP) with minimal consumption of oxygen relative to the blood flow measured per minute.
Comparative analysis with simulation A clinical safety STIO requires the availability of methods of Effective protection against interfering extrasystoles and variations spontaneous refractory areas of the myocardium that can be augmented by burst stimulation itself.
The importance and the speed of the variations of the refractory zones electrical and mechanical heart can be explained by the energy effort 20 that STIO requires each myocardial contraction.
The organization tends to avoid this effort, imposed by a very precise targeting of pulses in each cardiac cycle, altering both the durations and thresholds of excitability for these areas. But the simple adaptation, even perfect, to different myocardial parameters is not always enough to know the blood flow of each contraction because the variations of the parameters intrinsic (intracellular electro-mechanical coupling) of the device contractile remain unknown. It follows that an accurate, consistent analysis and comparison by a real blood flow "simulator", in real time, by compared to previous cycles with monitoring and possibility of intervention 3o automatic on the STIO remains necessary.
It should be known that in case of severe or acute heart failure the permanent maintenance of a STIO becomes more difficult and it is necessary to predict the evolution, especially in the short term, of cardiac parameters criticism. To this end, a memorization of the variations of the parameters that previously caused a risk of stall unjustified of the STIO and one stimulates so as to try to avoid such concordances; in case of a justified stall, for example arrhythmias or purely critical myocardial failure, the STIO will be programmed to stop instantly with alarm and parameter analysis responsible heart disease, and if necessary defibrillation or anti-inflammatory tachycardia or automatic injection of drugs. These security features can be provided by a "simulator-analyzer" (SIMA) using in particular the comparative analysis between, on the one hand, the ECG and simulated hemodynamic and / or metabolic patient, and, on the other hand, real recorded in real time and superimposed.
The invention of the STIO, adapting without delay to these various variatïons of spontaneous functional escapements from the heart, ensures a continuity of its optimal inotropic effect.
Theoretical simulation analysis adapted to each patient and his difference compared to the actual pattern of cardiac and vascular parameters in real time and deferred allows to show continuously the reactivity myocardial function towards pacemaker stimulation inotropic orthorhythmic. This STIO stimulation makes it possible to visualize instantly and to enlarge at will the differences between the layouts 2 o desired and the actual plots as well as their variations which allows, to his to readjust, if necessary, instantly and automatically parameters of electrical stimulation. It is thus possible to hatch, to to color differently and to quantify continually automatically the differences in subtraction of these plots. Manual readjustment can be as fast and often requires prior understanding of the physiopathological mechanism in question.
Given the information we have about the heart of a patient and its functioning, it is thus possible to establish a simulation of effects that we are theoretically entitled to expect by implementing the 3 o method according to the invention and compare this simulation and stimulation actually performed.
In this embodiment, the device comprises - means for acquiring information relating to the electrocardiogram of a patient, including the heart rhythm, - means for acquiring information relating to the hemodynamic performance of the patient;
analysis means responsive to said acquisition means for simulate the effect of a paired or inotropic coupled stimulation, adapted to the heart of the patient.
It advantageously also has means for automatically compare said acquired information relating to the hemodynamic performance of the patient to the simulated effect on said performance of an inotropic paired stimulation.
Preferably, which means of acquisition and of comparison allow the acquisition and comparison of information cycle by cycle.
Among the parameters for determining the state of the heart in a patient and its reactivity, we will remember his electrocardiogram in the state spontaneous or under the assistance of a pacemaker, for example a orthorhythmic pacemaker. We will also note information on the hemodynamic performance of the muscle and its reactivity to stimulations electric. The different parameters and means to acquire them, and especially for cardiac efficiency, including flow, volume and pressure, Oxygen consumption and others have been previously defined and are also described in the documents incorporated by reference.
Preferably, said parameters comprise at least one of the following parameters relating to contraction - slope (dp / dt) of the phases of rise and / or descent of the pressure intracavitary and / or intramyocardial;
- duration of the "plateau" of systolic pressure, corresponding to systolic ejection;
- duration of systole (cardiac contraction);
- duration of the diastole (filling phase, including initial phases motor, fast and slow);
- relationship between the durations of diastole and systole;
- quality of the diastole, especially filling depression;
- electromechanical coupling (duration separating the beginning of a complex QRS of the beginning of the mechanical systole it provokes).

Preferably, the device comprises means allowing a comparison of information relating to the electrocardiogram and the hemodynamic performance of a paired stimulation simulation or coupled inotropic, with corresponding information acquired during a actual subsequent inotropic stimulation identical or similar.
Preferably, it comprises means for acquiring or calculating a threshold level of values of performance information simulated hemodynamics adapted to the patient, and in case of exceeding the threshold, provoke a real stimulation, paired or coupled inotropic identical or similar.
Said means for acquiring the information relating to the electro-cardiogram of the patient and the hemodynamic performance of the patient, are arranged to acquire this information at different rates.
Preferably, the device is arranged to impose temporarily in the heart of the patient rhythms varying in stages or gradually, during which acquiring said information relating to the electrocardiogram and the said information relating to the performance corresponding hemodynamics.
Preferably, said means responsive to said acquisition means Are arranged to simulate the effects of several pairwise stimulations or inotropic coupled to different heart rhythms.
It is preferred to carry out said comparison for a limited number of cycles of the actual inotropic stimulation and, in case of finding of the absence a satisfactory level of hemodynamic performance, put an end to the stimulation in progress.
Said number of cycles may be, for example, of the order of ten or so or lower, especially 1, 2 or 3 cycles.
The device is preferably arranged for, in case of observation a sufficient increase in initial hemodynamic performance, continue the inotropic stimulation and detect and memorize whether the increase initial hemodynamic performance is maintained and / or increased progressively for a greater number of cycles.
Said larger number of cycles is preferably at least one hundred cycles.

Said analysis means can be arranged to include the effects inotropic drugs that may interfere with the effect of electrical inotropic stimulation.
The device may include means for visually highlighting and / or quantitatively by calculation, the differences between the curves of the simulation and the corresponding real stimulation.
Preferably, all this information relating to the electro-cardiogram, heart rate and hemodynamic characteristics or physiological, are obtained and stored in the device according to 1 o the invention, regardless of the spontaneous or stimulated heart rhythm of the patient.
In such a case, the simulation is refined by the analysis that is done in comparing the variations of the parameters, and in particular the parameters listed above, at different rates.
These changes in heart rate or responsiveness can also be acquired by subjecting the patient to the action of appropriate drugs acting for example on the rhythm and / or the contraction of the heart, by example dopamine.
So, for example, electromechanical coupling and how it may vary when the rhythm varies, will give a good indication of the Mechanical reactivity of the heart after stimulation. The slope of the climb pressure (dp / dt) will give an indication of the ability of the heart muscle to generate a rise in pressure while the slope of the descent of the pressure could be indicative of the compliance or elasticity of the muscular heart, and therefore its filling capacity during the diastole mechanical, according to the rhythm.
The device according to the invention is programmed to use the information thus acquired and propose, at least for the spontaneous rhythm or the patient's basic rhythm, and preferably for other rhythms, a electrocardiogram and a mechanogram simulating a result of a 3 o operation under a paired or coupled stimulation according to the invention.
A simulated mechanogram will thus make it possible to obtain, in particular, the simulated cardiac output, and we can then compare this simulated flow rate measured patient's spontaneous rhythm or simulated basic rhythm if there is place, and estimate whether the implementation of the inotropic stimulation according to the invention would result in a significant increase, preferably at least 20%, of the flow leading to a significant improvement of the patient in heart failure. The realization of simulations at different rates allows to estimate cardiac flow corresponding respectively to these rhythms and, where appropriate, to select a particular rhythm, for example 5 accelerated, for a heart failure patient with a spontaneous rhythm relatively low, or decreased, for example for a patient with a rhythm spontaneous high, which can be expected to decrease by inotropic stimulation according to the invention.
The following steps of the process according to the invention then consist in 10 to apply to the patient the inotropic stimulation chosen thanks to the step of simulation, to instantly acquire the results of this stimulation, and to compare these results with the theoretical results of the simulation.
The device is preferably programmed to check immediately the changes in hemodynamic performance at the end A very small number of cardiac cycles, for example during 1, 2 or 3 mechanical cycles, or during one or a few dozen cycles. Yes no significant improvement appears and is not maintained, for example after three cycles, the device stops the inotropic stimulation, or, according to done, try an inotropic stimulation under conditions 2 o different, for example at a different pace.
In the case where it is found, at the end of this low number of cycles, a first real improvement in hemodynamic performance, the Inotropic stimulation according to the invention is continued for at least one hundred or a few hundred cycles and the device checks if 25 the initial hemodynamic performance increase occurring all at the beginning of the inotropic stimulation, not only continues but increases even more gradually during this greater number of cycles and will be memorized.
The comparison between the simulated increase in performance 3 o Hemodynamics and the actual increase or modification of the performance hemodynamics can be obtained, for example, by superimposing the curves simulated and real hemodynamics and measuring differences, namely at least the flow difference, and preferably differences over others parameters, including some or all of the parameters listed above.

We could decide, for example, that if the difference, especially in flow rate, is negative and falls below a threshold, for example 10 or 20% below the value of the simulated flow, the stimulation inotropic process that has been implemented is not sufficient, the device then isotropic stimulation or trying another inotropic stimulation.
If, on the contrary, the increase in hemodynamic performance exceeds that simulated, for example by a value of at least 10 or 20%, may consider controlling the inotropic stimulation, for example in sending the paired or coupled stimulation pulses or bursts 1 o for certain cardiac cycles and not at each cycle where we can also use oxygen consumption indexes or other indexes as defined in the earlier documents incorporated by reference, in order to to verify that the increase in hemodynamic performance is not not at the expense of the availability of oxygen for the patient.
Moreover, according to the improvement of the invention, the results electrical and mechanical aspects of the inotropic stimulation according to the invention will be registered and treated with those previously acquired to carry out the simulation, in order to further clarify the particular characteristics of the heart of the patient as defined, for example, by the different Above mentioned parameters, which will then make it possible to obtain electrocardiograms and / or electromechanical simulation curves Selected.
Especially when STIO is applied to patients suffering from severe or acute heart failure, we observe that STIO can be impossible to start or get off the hook during operation.
In order to anticipate and oppose these serious incidents, it is necessary to analyze precisely the cause of these non functioning of the STIO. This is often of an adequate non-superposition between the refractory zones Electric (ZRE) and Mechanical (ZRMM) which can shrink or move relative to each other in such a way that the duration of the critical zone effective (ZCE) is virtually canceled or more frequently reduced, by for example, at 10 ms. In this case, if the stimulus salvo of the STIO is consisting of pulses whose interval is 15 ms, it becomes impossible to provide continuous inotropic stimulation and the patient is exposed to a depletion of its oxygen reserves.

According to a variant of the invention, and in order to avoid this failure of the STIO, it is necessary to measure accurately with same place of the heart, and as needed permanently, the durations and temporal overlays of these ZRE and ZRMM; this function can be provided by the simulator-analyzer (SIMA). When SIMA registers a critical shrinkage of the ECA, it can automatically, without delay, bring the impulses of the bursts properly together so as to try to regularly target at least one pulse within the ECA.
In case of impossibility to regularly reach the ECA, the SIMA
1 o Stops, by program, without delay, the STIO. A permanent rapprochement pulses to each other below 10 ms prevents, in the current state of electronics, ZRE measurements and other disadvantages electronic and possibly physiological.
Preferably, the device comprises - means for continuously measuring, in a location of the heart, ZRE electric refractory zone, means disposed substantially in the region of the heart for accurately measure areas of maximal myocardial contraction ZRMM, the device being arranged to acquire, from said means, the temporal superimposition, in the same cycle, of said zones ZRE and ZRMM and determine the zone not common and posterior to the zone ZRE, known as ZCE critical zone.
The electrical stimulation means are arranged to address ~ 5 immediately at least one stimulation pulse in said region of heart during said ZCE zone.
According to an improvement, said means verifying the superposition time are sensitive to an offset between ZRE and ZRMM zones for send a stimulation pulse or a burst providing at least one impulse inside the ZCE zone.
Preferably, said sensitive means make it possible to reduce the time interval between two pulses of a salvo to increase the probability of having a pulse during said ZCE zone.
Preferably, the duration between two pulses of a burst can not be reduced to less than a value of the order of 10 ms.

Preferably, if it is impossible to send at least one pulse inside the ZCE zone, the device stops the stimulation coupled or paired.
According to an improvement, the device stores the events and the time periods of the ZCE zones during a plurality of cycles and analyze their evolution to foresee a possible tendency to the suppression of said zone ZCE and, in this case, to implement a treatment, in particular by infusion of drugs or modification of the rhythm of STIO
in order to act on the duration of ZRE or ZRMM zones or their overlap.
The means used by the device according to the invention are, except if they are otherwise described, means which, in their individuality, are classical in the art, and described, for example, in the various documents incorporated by reference.
Thus, the acquisition means associate electrodes, sensors physical or biochemical known to means of shaping signals and computer processing means, including micro processors and memories, with software that the person skilled in the art knows or can produce routinely, from the moment he reads the described operation of the invention. The same is true of the means 2o works for stimulation, including their source of electrical energy, and of the sensitive computer processing means, for example, at rhythms, durations, detection thresholds and electrical curves or hemodynamic or biochemical acquired or produced.
The invention also relates to methods for treating or prevention of cardiac disorders including the successions of the stages described above, these methods using a device such as described in the present invention.
Thus, the invention, in a first mode of implementation, has as its object a method of electrical stimulation of the heart, in particular for treating 3 o or to prevent heart failure, and in particular insufficiency left ventricle, or tachycardia, arrhythmia or significantly increase a hemodynamic performance of the heart, said process comprising the following steps implant a stimulation device as described herein The invention;

- automatically acquire information on the heart rhythm, preferably, by acquisition of the electrocardiogram, preferably accelerated progress;
- determine, preferably at each cycle, preferably in time real, the duration of the electrical refractory period (ZRE) following the last R-wave of the current cycle or of another close previous cycle;
- and, in the next cycle, address substantially without delay before the end of said refractory period (ZRE) determined at least one pulse of stimulation, and preferably a stimulus pulse burst, for cause a significant prolongation of the refractory period (RZ) without cause no mechanical stress.
In a second embodiment, a method according to the invention for the stimulation of the heart muscle, in particular for one of the aforementioned conditions, comprises the following steps - automatically acquire information on the heart rhythm, preferably, by acquisition of the electrocardiogram;
- preferably, determine each cycle, preferably in time real, the duration of the electrical refractory period (ZRE), which follows the latest R wave of the current cycle or another previously close cycle;
- send, in the following cycle, substantially without delay at the end of the said refractory period (ZRE) determined at least one pulse, preferably a salve of stimulation;
- automatically acquire information on hemodynamics heart rate, preferably the pressure / volume curve of contraction heart;
determining the strengthening of said hemodynamics;
- in case of no or too little reinforcement, change the moment of sending and / or parameters of said pulse or burst until obtaining a higher degree of hemodynamic performance.
3 o In a particularly preferred mode of setting poor, it is used means (4) for determining the duration of the refractory period (ZRE) sensitive to the detection of that of the pulses of a salvo which triggered a complex R 'and means of determining the area maximum mechanical refractory ZRMM, and it is determined in said area ZRMM, a zone ZCE posterior to the electric refractory zone ZCE, and if said zone ZCE is existing, one addresses at least one pulse of stimulation in said ZCE zone.
In a particular embodiment of said methods of the invention, the heart is allowed to generate (a spontaneous electrical systole R which 5 causes contractions of the heart muscle. Sending the impulse or the salvo or train of pulses shortly before the end of the said refractory period can then be said "paired" with said spontaneous electrical systole R.
In another embodiment, which can then be used and possibly in addition to the previous one and in particular in case of 10 bradycardia, or for the orthorhythmic reduction of tachycardia, we regularly send to the heart a stimulation impulse intended for cause a stimulated electrosystole R causing contraction myocardial and one sends the coupling pulse or the stimulus burst according to the invention substantially without delay at the end of the refractory period, the 15 heart then being stimulated at an electrical rhythm, said pulse or salvo of stimulation is then said to be "coupled" to the electrosystem.
In the methods according to the invention, the determination of the duration of the electric refractory period (ZRE) can be obtained by the steps such described in connection with the operation of the device according to the invention, by 2 o example by calculation and / or by scanning, and / or measurement.
In a particular embodiment of the methods according to the invention in which a burst of impulses is sent, the salvo of impulses is sent a little before the estimated end of the period refractory (ZRE), the duration of the salvo and the number of impulses being 25 electrical stimulation will occur very soon after the end of refractory period (ZRE).
In an improved embodiment, the detection of impulses of the salvo that triggered a wave (R ') that prolongs the duration refractory (ZRE) and, if applicable, the following cycle, at least one Characteristic of the salvo.
These characteristics include the start time the burst, its duration, the number of pulses, the interval between pulses, and the intensity of the pulses of the salvo.
Preferably, anti-pacing means are also used.
tachycardia and means sensitive to extrasystoles to stop automatically programmed stimulation in case of occurrence of a excessive hemodynamic instability or severe electrical arrhythmia meeting pre-selected criteria.
In addition to the rhythm acquisition means, it is possible to use the means determining the refractory zone duration and the means for sending a impulse or salvo, means (7, 10) sensitive to the precise acquisition hemodynamics to determine variations in efficacy of hemodynamics, these means being capable of controlling the sending and possibly the parameters of the pulse or burst, preferably 1o in a way close to the one that produced hemodynamics, the most favorable for the patient at some point.
Said means act on parameters such as: a rhythm programmed ventricular and / or automatic start or end or the duration of the salvo or the number or characteristics, including width, intensity, polarity, density, pulse interval in the salve, or still a location of sending the salvo on one or between different stimulation electrodes.
Preferably, metabolic parameters are acquired, in particular . oxygen consumption and / or its equivalents, such as the measurement of 2 o myocardial cell membrane electron densities, or increase ketone bodies, lactic acid, etc.
In an improved implementation of the process, an address is impulse or a salvage stimulus within the zone (ZRMM) located at inside the plateau of the contraction curve of the mechanogram and during which the contraction of the myocardium is substantially maximal.
Thus, the impulse or at least one pulse of a burst of stimulation, falls into said ZRMM area. Preferably, one acquires said zone (ZRMM), automatically.
In one embodiment, the intracavity pressure is measured 3o by a sensor and one detects and chooses a zone of maximum pressure in the systolic plateau of the cardiac mechanogram in which one causes a stimulus pulse or burst to be sent.
But, preferably, the local intramyocardial pressure is measured near a sensing and stimulating electrode.

Preferably, the myocardial pressure is detected in the septum intra-auricular and / or intraventricular.
In another mode of implementation, the variation of volume of the heart, or part of the heart by detecting the area where said volume has reached and maintains its minimum value.
The subject of the invention is also a process in which we acquire information about the electrocardiogram of a patient, including heart rate, - performance information is acquired hemodynamic patient;
- and we use this information to simulate the effect of stimulation paired or coupled prolonged inotropic.
The acquired performance information is compared hemodynamics of the patient to the simulated effect on said performance of a inotropic paired stimulation.
Preferably, the acquisition and comparison of information cycle by cycle.
Preferably, at least one of the following parameters relating to to heart contraction - slope (dp / dt) of the phases of rise and / or descent of the pressure intracavitary or intramyocardial;
- duration of the "plateau" of systolic pressure, corresponding to systolic ejection;
- duration of systole (cardiac contraction);
- duration of the diastole (filling phase);
- relationship between the durations of diastole and systole;
- quality of the diastole, in particular depression of filling or speed and amplitude of the phases fast and slow;
- electromechanical coupling (duration separating the beginning of a complex QRS of the beginning of the mechanical systole it provokes), - shift between the local intramyocardial contraction curve and the global ventricular intracavitary contraction curve.
We then compare information about the electrocardiogram and the hemodynamic performance of a paired stimulation simulation or inotropic coupling, with corresponding information acquired during subsequent identical real or similar inotropic stimulation.
Preferably, a value threshold level is acquired or calculated information on the simulated hemodynamic performance of the patient, and if the threshold is exceeded, a real, paired stimulation is triggered or identical inotropic coupling or the like.
Preferably, the information relating to the patient's electrocardiogram and, to the performance and hemodynamics of the patient, at different rates, including increasing or decreasing stages or gradually.
Preferably, means sensitive to said means are used.
of acquisition arranged to simulate the effects of several stimulations paired or inotropic coupled to different heart rhythms.
Preferably, the comparison is made during a number of limited cycles of the actual inotropic stimulation and, in case of finding of the absence of a satisfactory level of hemodynamic performance, it is end to the current inotropic stimulation.
If there is evidence of an increase in performance initial hemodynamics, the stimulation is preferably continued.
Inotropic and detects whether the increase in hemodynamic performance initial maintenance and / or increase gradually larger number of cycles.
The effects of drugs may be used in the analysis for the purpose of Cardiovascular previously administered or being administered.
Preferably, one emphasizes visually and / or quantitatively, in particular by superimposing the curves, the differences between the curves simulation and stimulation.
Preferably, the cardiac mechanogram is acquired, in particular until the appearance of a cycle long enough to obtain a good contraction 3o myocardial, and then sends a pulse or salve of stimulation to an instant located inside the plateau of the mechanogram curve (ZRMM), especially a little before the end of the electric refractory zone (ZRE) after which it stimulates immediately after the end of the refractory zone electric which will cause a new electric refractory zone.

One can advantageously define a first threshold of increase of overall hemodynamic performance / min and / or cardiac contraction, cardiac output, said threshold being equal to at least 15% or preferably 25% of the pre-treatment performance, and the parameters of the stimulation until at least said value of threshold.
If the increase is not obtained according to said first threshold value during a period of the order of 1 to 10 contractions, it is preferred to stop the treatment.
The subject of the invention is also a method for treating a acute or severe heart failure in which - the heart rhythm is automatically acquired, and in particular the interval between at least the last two R waves (caused or spontaneous) of a cardiac cycle that has just ended, - the duration of the period is preferably determined continuously electrical refractory (ZRE) following the last R wave of said cycle, - address substantially immediately, at the end of the refractory period (ZRE), at least one stimulation pulse and, preferably, a salvo 2o stimulation pulses, the duration of the burst then being such that, account given the interval of repetition of the pulses in the burst, an impulse of salvage stimulation is addressed to the heart substantially without delay after the end of the refractory period, and - these steps are repeated during a series of least three contractions if there is a first improvement in the heart performance, - and, in the absence of an improvement, we automatically stop process.
The mechanical performance of the core is advantageously compared 3 o total including blood flow and / or volume variation ventricular, on the one hand, before the implementation of the process steps and, on the other hand, after the implementation of the process steps, and if the increase in performance of the heart is greater than 15%, we again implement the process steps;

The subject of the invention is also a method of resuscitation heart failure in a patient with severe heart failure or criticism in which - the heart rhythm is automatically acquired, and in particular The interval between at least the last two R waves (caused or spontaneous) of a cardiac cycle that has just ended, - the duration of the period is preferably determined continuously electrical refractory (ZRE) following the last R wave of said cycle, - address substantially immediately, at the end of the refractory period (ZRE), at least one stimulation pulse and, preferably, a salvo stimulation pulses, the duration of the burst then being such that, account given the interval of repetition of the pulses in the burst, an impulse of salvage stimulation is addressed to the heart substantially without delay after the end of the refractory period, and - these steps are repeated at least until at least a gradual improvement in cardiac performance detectable.
Treatment or resuscitation procedures may advantageously also use the other steps of the processes described 2 0 previously.
The subject of the invention is also processes for treating or prevention of cardiac arrhythmias including spontaneous, implementing the steps listed above for the application of the opposing device 25 to arrhythmias. It also relates to methods of treating or prevention of cardiac arrhythmias caused by, or associated with, the of a device according to the invention, said method implementing the corresponding steps listed above.
30 Regeneration of the myocardium The subject of the invention is also a regeneration method physiological and / or anatomic and especially cellular myocardium in the insufficient heart muscle, which method comprises preferably, the steps described above.
Such a method according to the invention comprises the following steps implant in the heart, for example in a right atrium or left and / or right or left ventricle, regeneration cells, in sub-endocardial or intramyocardial position, preferably in several groups of cellular or cellular clusters, and provide stimulation according to the invention, preferably a paired stimulation.
Such another method according to the invention comprises the stages following - obtain and cultivate, in vitro, regeneration cells, 1 preferably in the form of small clusters, - put these cells in electrical conduction contacts between them and with an electrical stimulation device, - periodically send electrical pulses to said cell - detect the responses of depolarizations and repolarizations electrical or potential membrane cell cultivated cells, said cell being intended to be implanted in the carur, preferably in several groups or layers of cells, in the subendocardial position or intramyocardial, once their electrical detection by micro-electrodes 2 o intracellular will have shown the ability of cells to an activity electromechanical rhythm adapted to the myocardium of the recipient.
Stimulation can be a simple electrical stimulation to a rhythm, preferably of the order of a normal heart rhythm. She can, from preferably, after an initial period, be sent in a paired form or coupled, once clusters or groups of cells in culture are synchronized and exhibit an acceptable electrical refractory period by myocardial report of the recipient.
The cultured cells can be of any type, for example muscle, myocardial, embryonic or stem cells or 3 o totipotent or multipotent.
These cells may also have been obtained by a method in which is transferred to a functional oocyte or stem cell totipotent or multipotent or embryonic, a nucleus or part of nucleus or foreign chromosome or genes, and this material is removed at an uncompleted stage of mitosis to transfer it into a cell, preferably original or autologous, totally or relatively differentiated.
Regeneration can also relate to vascular parts, for example coronary, implementing such means, with a adapted stimulation or coronary function.
In order to accelerate and prolong their multiplication in vitro or after transplantation, these cells, or some of them, for example myocardial or muscle precursor cells, or others, may be genetically modified to overexpress telomerase or Sir2 protein, 1 o in particular by transfection with a viral or retroviral vector, or other vector, the telomerase gene or Sir2 reverse transcriptase protein (hTERT), using for example the technique described by Steven Goldman, Nature Biotech., February 16, 2004.
The STIO according to the invention is also applicable to regeneration, less partial, cardiac muscle, especially in the heart failure chronic or acute by implementation of STIO, even in the absence of adding cells, continuously or periodically, for a period of long, for example from a few weeks to several months or more.
The subject of the invention is also a process for the preparation of cells living organisms, in particular plant, animal and human, likely to be relocated for prophylaxis or therapeutic purposes, in which the transport in an oocyte, preferably unfertilized or recently fertilized, homologous or heterologous mammal, previously preferably completely or partially emptied of its nucleus, of a nucleus of a dedifferentiated cell, so as to induce a mitosis stage of said transferred nucleus, in that this nucleus is removed during mitosis and before the end of it, then we introduce this partially dedifferentiated nucleus in mitosis at this stage in a cell, preferably after having 3 part or all of its nucleus (s) so as to induce and finish his nuclear division of differentiation and form a cell strain or a tissue at a stage of differentiation less advanced than that of said cell differentiated.
The transferred nucleus can be extracted at the stage of metaphase, The anaphase, prophase or telophase of the first mitosis.

A myocardial cell nucleus can be transferred to the oocyte, heart muscle or autorythmic, including sinus cells, Tawara center or beam fibers of His or Purkinje.
The partially dedifferentiated cells obtained can be subjected to preferably after or during their cell multiplication culture after the formation of a confluent set, to a periodic electrical stimulation cardiac stimulation type, in particular according to the stimulation method of the invention.
Preferably, said cells are subjected to electrical stimulation 1 o coupled or paired in which this impulse without any effect contractile is sent shortly after the end of the electrical refractory period of cell in culture.
For example, these cells are subjected to electrical stimulation in cycles including a first stimulation pulse and, to the end of the refractory period, a train of impulses, so that one at less impulses of the train falls shortly after the end of the refractory period electrical cells and during their mechanical refractory zone of maximum contraction.
The cells obtained by this method can be implanted at the level of the Atrial myocardium, particularly in the case of a patient suffering from atrial fibrillation.
The subject of the invention is also an arterial segment or stent, in particular coronary, aortic, carotid, renal or femoral, including a structure coated or colonized by cells obtained by the methods according to the invention, preferably consisting of living cells, self-contractile and elastic, especially autologous, cultured according to the process.
This segment or arterial stent can be shaped like a stent arterial arranged to be introduced into an arterial lumen.
Preferably, it comprises means providing stimulation 3o electric arterial type, coordinated with the ventricular diastole, said cells of the segment, for example at least one stimulation electrode and / or detection.
The stimulation and / or detection electrode has preferably been introduced into the cell culture to be surrounded by said cells 3 5 alive.

The segment or stent may comprise a sensor, in particular measurement of oxygen saturation and / or metabolic parameters, and a electrocardiographic sensor for detection or stimulation.
It may have a plurality of electrodes arranged to obtain the variations in the local electrical impedance.
Preferably, it comprises a structure, in particular mesh expandable supporting different cell layers, such qu'atreartère, myoarter and periarterium, said structure allowing a spontaneous growth with progressive enlargement of its light and 1 o creation of a nourishing vascularity including the part myoartérielle.
The structure is made, for example, in at least one of the materials following: PLGA, collagen, globin, for example by knitting.
It is also possible to provide an arterial stent without living cells having a radially expandable structure, but rigid enough to keep the arterial lumen open at least in systole, possibly biodegradable or removable by catheter and capable of receiving a stent physiological as described.
Finally, the subject of the invention is a biological cardiac pacemaker comprising cardiac autorythmic cells or tissues, partially 2 dedifferentiated, according to one of claims 110 to 122, preferably autologous, homologous, from the recipient organism, and intended to be implanted in the heart or a failed region of the heart.
The invention is described below with reference also to FIGS.
annexed in which FIG. 1 schematically represents an electrocardiogram associated with a myocardial mechanogram corresponding to the functioning of a device according to the invention, FIG. 2 represents a view of a real example, FIG. 3 shows the acquisitions of various parameters in the operation of the invention, FIG. 4 represents a schematic view of a device cell implantation, FIG. 5 represents a schematic view of the synoptic type of a device according to the invention, FIG. 6 represents a schematic view of a device according to Figure 5, further presenting additional means.
FIG. 7 diagrammatically represents the electrocardiogram and mechanogram of a STIO according to the invention for a slow spontaneous rhythm, FIG. 8 diagrammatically represents the electrocardiogram and mechanogram of a bradycardic STIO, - Figure 9 schematically shows the different areas electrical and mechanical distinguished in the invention, FIG. 10 diagrammatically shows electro-cardiograms 10 and mechanograms implemented in the simulation according to the invention, FIG. 11 represents a control and display panel of a device according to the invention.
Figure 1 shows an example of the operating principle of a Device according to the invention. The top line shows the ECG, the line median shows Y couplings of orthorhythmic bursts versus R-waves basal rate, that is, as a percentage of the duration of the previous cycle Z
and the lower line shows the myocardial mechanical activity. R waves full represent spontaneous or stimulated depolarizations and 2 0 Dotted RV waves the basal R-waves inhibited by the extension artificial (RZ) refractory zones induced by bursts of pulses electric. Bursts of five stimulator pulses according to the invention are clearly visible on the ECG and the first pulse of each salvo, which causes the depolarization, allows the measurement of each Functional refractory zone (ZRE or RZ) in each cycle. It takes to note that the beginning of the non-refractory electrical zone (ZNRE) precedes the beginning mechanical non-refractory zone (ZNRM). On the mechanogram, the ZRMM interval corresponds to the period of the systolic refractory zone maximum active contracture during which electrical stimulation 3 o propagated causes practically no effect or energy expenditure myocardial because this muscle, being in maximum contraction just before its active relaxation, is incapable of any other biological action spender.
The ZRMM is followed by the mechanical non-refractory zone (ZNRM). It takes know that any electrical stimulus occurring immediately after the ZRMM, For example 20 ms later falls into ZNRM zone and can already provoke a biochemical early energy recharge reaction, for this diastole and beginner, resulting in oxygen consumption even in the absence of any mechanical activity perceptible by current instruments.
The ZRM or ZR interval corresponds to the mechanical refractory zone preceding the narrow ZRMM zone. The ZRMM zone is only one small portion of the top of the ventricular systolic pressure curve.
The reference D designates the electrical diastole.
The static description above of the functional areas of each heart cycle does not show the actual dynamic course at a level 1o myocardium suffering. In reality, the different functional areas and ZRE and ZRMM may vary from one cycle to another, for example between 15 and 80 ms; this partly already favored by drugs cardio-active, vegetative tone and pre- and post-charges trans-membrane fluxes and other intracellular metabolisms. We now understand why classic paired stimulation that uses only one electrical pulse to extend the ZRE, with an interval constant coupling in ms., can not realize a security STIO
because the only fixed-coupling stimulus will sometimes fall before, during or after the moving critical interval, which remains invisible on an ECG
normal.
The result is physiologically inconstant, visible cardiac stimulation.
only on special ECG high speed unwinding and on very precise intracardiac mechanograms (which is not the case in classical coronary angiography) and certain metabolic demands, causing an overconsumption of oxygen that is harmful to the myocardium, hemodynamics and eurhythmia, which is wrongly attributed to the only paired stimulation.
During the STIO cycles treated by the invention in paired stimulation or coupled, can vary not only the durations of the refractory zones, but also the thresholds of excitability. To compensate instantly and 3o continually these irregularities, it is necessary to have a device automatic readjustment of these thresholds well known at the pacemakers implanted and first described by the inventor in French Patent No. 1,237,702, PV No. 651,632 of July 11, 1953. It can be useful to launch periodically and automatically on demand, according to the frequency of critical variations of the observed thresholds, bursts orthorhythmics whose voltage varies gradually or not and whose effects on the electrical depolarization caused will be automatically taken account to readjust, for example, to the next cycle concerned the intensity pulses composing each salvo. This pulse intensity can also vary regularly or not from one pulse to the next or periodically inside each salvo of the STIO. In case of certain significant variations of these thresholds of excitability or refractory zones, he It is desirable to check automatically if the variations concern only one of the parameters and which one or both parameters vary 1 o jointly and how. These controls also make it possible to react preventively and instantly if it is impossible to continue stimulation (STIO) according to the invention as programmed, for example in case of metabolic disorders (lack of local beginner oxygen, tendency to arrhythmias, decrease in hemodynamics, etc.). In more cases of STIO, which is stable enough, it can be example, automatically decrease the number, the density (several electrodes or a large surface emitting electrode focusing on a receiving electrode), the width or intensity of the pulses of each salvo of the new orthorhythmic pacemaker and conversely increase them in case 2 o increasing instability. We can thus obtain an exploration Automatic from each cardiac cycle constantly adapted to its own evolutions Pathophysiology to prevent, treat and report instantly many heart failures that otherwise would reveal more or too late. In addition, this method can make it possible to control instantaneously some implanted drug pumps (Zacouto, US Patent 5,305,745) and if one has several electrodes, preferably far enough, stimulation in the heart (eg stimulation of ventricular resynchronization) a sufficient and sudden difference between these refractory areas and thresholds of excitability may indicate thrombosis 3o coronary or local myocardial lesion. The diagnostic functions of the STIO according to the invention can alone justify its application, by example, when using drugs that influence cardiac function if necessary, cutting the stimulation functions.

The clinical use of STIO should be distinguished according to whether it is applied to tachycardia or myocardial insufficiency. In the case of poorly supported, rebellious or recurrent tachycardia, STIO
the installation of cardiac stimulation electrodes, to reduce first quickly his pace by ~ about two with an increase considerable and immediate impact on cardiac output, which is due in part to great prolongation of the diastole and secondly to the EPR which is added to it.
In some clinical cases, including ventricular tachycardias (TV), it is possible to remove these tachycardias by cutting their circuits 1 o re-entered by the adjustable orthorhythmic bursts of the STIO which can automatically target the least myocardial spaces not yet in refractory phase during ectopic depolarizations. It is not enough always to submit a TV to STIO to reduce it, but once installed, it should vary its orthorhythmic parameters, for example to bring together intervals between pulses, their numbers, intensities, widths, percentage of coupling with respect to the duration of the previous cycle, etc. of the bursts and, if necessary, bring the stimulating electrode closer to the ectopic activations; all this can be done and remembered automatically for example compared to the marking spikes of detections and stimulations of the orthorhythmic pacemaker (ORP) if one has several electrodes to avoid an electric shock.
In the case of acute or chronic heart failure not caused by fast ectopic tachycardias, which are often moderate sinus tachycardia, the STIO immediately leads to decrease in rate (eg from 100 to 60 per minute and one significant and lasting increase in cardiac and coronary that an immediate and persistent decrease in pulmonary arterial pressures.
In case of irreducible or recurrent tachycardias, especially TV, we can reduce their rhythm by two using a permanent STIO, this 3o which can be an alternative to ablation or allow to wait, without danger for the patient, ablation in excellent hemodynamic conditions, what even the return to the sinus rhythm can not reach. At the carriers of an implanted automatic defibrillator (ICD), one can, in case of occurrence of a dangerous, resistant or recurrent tachycardia classical orthorhythmic anti-tachycardia pacing, switch first on a STIO and only if, after about 10 seconds, a good hemodynamic is not restored, trigger the shock of defibrillation; this procedure will remove painful shocks. In the case of Acute or chronic heart failure, not caused by fast ectopic tachycardias, which are often in sinus tachycardia moderate, the STIO immediately leads to a significant increase cardiac and coronary output and a persistent decline in pulmonary arterial pressures. Another advantage of the implanted STIO
is that it usually allows the patient to resume an activity 1o very increased physics. The sudden and significant increase in the hemodynamics caused by STIO can be a disadvantage for some patients, in these cases the STIO can be programmed to launch its bursts or pulses extending ZRE zones for example, only on a R wave spontaneous or stimulated on three or four instead of one on two or even decrease the duration of diastoles by accelerating the rate of based. For example, you can automatically switch the mode of paired stimulation of STIO in coupled stimulation, by the intervention of a program imposing a strictly limited increase by a threshold selected. A coupled stimulation is a stimulation without any R wave 2 o spontaneous at a rate totally imposed by the STIO. These two modes can be done automatically by controlling them against the parameters the desired hemodynamics and preferably by controlling the changes concomitant metabolic processes such as oxygen consumption.
Another known advantage of salvos of orthorhythmic impulses used by the STIO is that on a salvo, for example, 4 pulses consecutive squares with a duration of 0.5 ms each at 1.4 volts with a interval of 15 ms between the pulses, if the second pulse causes the depolarization, the following impulses will rapidly exceed of propagation exceeding Km / sec) a possible beginning fibrillation locally for less than 15 ms (propagation speed around 70 cm / sec) and surround it with a refractory zone; moreover, the first impulse of the salvo that falls in ZRE eliminates the spread of possible depolarizations of some earlier cells invisible on the ECG but sometimes can start an arrhythmia.

In addition, STIO immediately improves coronary flow especially by the intervention of the EPR and the diastole very elongated as this is known in coronarography as well as by the motor start of the diastole which is increased in proportion to the increased shortening of the Myocardium caused by the increased contractility, which corresponds to a strong increase in myocardial visco-elasticity during the phases motor skills; this viscoelasticity is measurable, for example, by a detector multi-axis pressure implanted in the myocardium, such detectors being known. The concomitant decrease in pulmonary arterial pressure is 1 o Most likely due to increased cardiac output. In theory, the STIO should not result in a significant additional expense oxygen. The significant slowdown in ventricular rhythm decreases this oxygen consumption while increasing contractility despite improved energy efficiency requires additional oxygen.
15 Some increase in oxygen consumption during STIO
also corresponds to an increase in cardiac flow rate ratio oxygen consumed; the surge in coronary flow will allow the most often to tolerate this extra expense of oxygen.
At even greater hemodynamics, STIO consumes less oxygen than 20 other heart rhythms. There are ventricular rhythms spontaneous extrasystolic to optimal hemodynamic functioning as a artificial paired stimulation as if the maximum contraction causes a electrical extrasystole targeted to protect the myocardium of a next contraction too close (fig 2) recorded by the inventor and published (Dtsch.
25 Gesellsch. Kreislauff. 29 Tagung, p 255-261, 1963 Steinkopff Verlag Darmstadt). Another example of a spontaneous rhythm resembling a Paired stimulation is electro-mechanical decoupling, one out of two QRS, in cases of rapid tachycardias; this phenomenon can last for years and patients often go well and are surprised when they are told Tachycardia.
The STIO according to the invention aims to take optimal control rhythm and contractility of the heart, on the one hand, occupying the whole first electrical non-refractory zone beginning of a cardiac cycle and, on the other hand, trying to ensure optimal contractility and speed Blood volume per minute desired; this last claim requires a control in real time geometric. and / or volumetric and energy of at least one cardiac ventricular cavity. For this purpose and for a POR with STIO, implantable or not, it is preferable to provide a very demanding device little example of measuring type of electrical impedances within the heart. The parameter of the sequence of volumetric variations is preferably supplemented by that of intracavitary blood pressure and / or intra-myocardial concomitant to reproduce a curve correct pressure-volume, preferably displayed on the outside of the body by classical telemetry. For such a programmable stimulator in automatic, lo can be realized an electronic device which integrates, for example, the area pressure curves and if possible volumes or speeds and flow rates corresponding blood pressure (for example, by type of impedance intracardiac electrical), compared to the programmed ventricular rhythm, and which then imposes a rhythm close to the value that has detected the most favorable hemodynamics for a given patient at a time given, after having performed, memorized and compared these obtained values after a certain sweep of the frequency (Zacouto, US 5,306,293). More, an automatic adjustment of the pulses constituting the stimulus burst orthorhythmic with respect to hemodynamics and / or consumption 2 o oxygen can vary the number of pulses, their interval that can to be non-equidistant, their width, shape, polarity, intensity and their voltage that can also be unequal as well as the location of their application at the heart level. This location of their application can have fixed monopolar, bipolar or multipole stimulations or variable, with atrial or ventricular endocavity electrodes, intra-myocardial, epicardial or intravenous coronary, intra-arterial coronary, intra-stents such as special stents with ECG electrodes and / or stimulation with or without hemodynamic sensors, saturation oxygen and / or CO2, pH, blood glucose or other metabolic indicators. For 3 o avoid a large energy expenditure of the electronics of these devices implanted, a small HF antenna can be installed on each side of the skin that transmits additional energy when the device uses special therapeutic sensors and effectors.
The control of the heart rate that the STIO gives according to the invention has the ability to accelerate and slow down an accelerated heart, which also distinguishes it from classic cardiac pacemakers. In case of relative bradycardia induced by STIO, non-refractory electrical phases are not prolonged as much as with spontaneous bradycardia. when It is not possible with the paired stimulation to obtain a desired accelerated ventricular rhythm, STIO can automatically switch to ventricular coupled stimulation, which removes any QRS complex spontaneous and allows to obtain an effective ventricular rhythm which is the half fast paced ventricular rhythm. One can also, if the atria and the Hispanic conduction is normal, as has been done successfully 1o out of two patients in heart failure, train the atria to a fast pace of around 160%. min and get a STIO ventricular to 80 p. min, which makes a trained ventricular QRS persist but almost normotropic in its activation, seen from the ventricle.
Apart from regular tachycardias, phase reduction non-refractory in the myocardial space produced by STIO and its adjustments gives this cardiac stimulation an anti-arrhythmic effect especially to eliminate premature ventricular premature beats. In case of atrial fibrillation (AF) the ventricular STIO may allow protect the ventricles of AF influxes totally for AF influxes which Early fall into the ventricular cycle (CV) and partially to impulses occurring later in the CV, if necessary by potentiating with certain drugs slowing the Hispanic conduction, which gives back to ventricles a sufficiently regular rhythm, for example eliminates all resumes less than 600 ms., partly adjustable and accompanied by contractility optimal; this can compensate and overcompensate for the adverse effect of FA
on myocardium tired by tachyarrhythmias and coronary flow low and potentially potentiate the effect of Digoxin and other cardioactive drugs.
You can also stimulate a ventricle around 150 puls./min and get STIO according to the invention a regular effective rhythm towards 75 puls./min well tolerated and immune to the influx of AF. An auricular STIO increases at maximum atrial contraction and strengthens muscle power, opposes its dilatation, thrombosis, relocation of certain FA
(atrial fibrillation) and improves ventricular flow and coronary if STIO parameters are well adjusted to activations auricular and ventricular, natural or artificial. A stimulation auricular can, for example, be performed in bipolar from electrode placed on the upper half of the atrial septum, which may help to synchronize the atria without disturbing the ventricles. A double STIO, coordinated atrial and ventricular, maximizes contraction Coordinated atrial and ventricular can be very useful, with Hispanic or not, to increase considerably without delay and long time cardiac hemodynamics.
Any STIO adapted according to the invention regenerates a functioning genetics with inotropic effect of the myocardium with modifications of the expression development genes, ion channels and functions contractiles induced by mechanical and metabolic constraints increased imposed; these will lead to its intracellular remodeling functional recovery, for example in case of heart failure (dilations) or necrosis (shrivelling). This etiological therapy of every heart failure can give a rapid genetic involution of its pathological process and genetic modification of regeneration physiological and anatomical caused by the effect of very contractility increased to the specific evolutionary possibilities of each patient, 2 o adapting automatically to each particular case, except where certain diseases such as metabolic, tumoral, viral, toxic etc.
prevent myocardial function from recovering The maintenance of recovery of cardiac function requires muscle activity sufficient peripheral that should be coordinated with the action 2 central myocardial STIO.
For certain necrosis or extensive fibrosis of the myocardium, is considering autologous local stem cell transplantation multiplied and differentiated in vitro or genetically transformed cells or reprogrammed by electrical mechanical and biochemical drive 3 o able to recolonise destroyed sites and to metabolize certain tissues scar.
We can proceed to the simple local recolonization of isolated cells partially dedifferentiated myocardium, which is a syncytium, cells genetically oriented towards rhythmic and contractile functions with 35 refractory zones, which can easily, under the effect of the environment, organize themselves into mechanically efficient networks well coordinated with the heart.
Preferably, a preliminary programming of the STIO is added.
The in vitro multiplication of the cells to be transplanted must not be done always to the immobile state, but preferably also, under mechanical stress controlled alternation adapted to the future functions of cells and capable of to induce an electrophysiological membrane state compatible with the function of the heart to serve, and preferably controlled by a STIO adapted to functional capacity of cells to genetically orient them towards their future contractile function, and this, if possible, with serum Autologous.
In addition, these cells should be encouraged not to multiply separately but, for example, to form small functional structures in three dimensions by cultivating them, for example, on a preformed matrix, porous, elastic and biodegradable such as PLGA and PLA (acid derivatives poly-lactics) to prevent their dissemination after their injection and promote their contractile function in syncytium coordinated with the stimulation of heart. The small preformed matrices can have 3D shapes that promote their mutual assembly and with the myocardium of the recipient, by example in the form of strips, discs, squares, crosses, 2 o coils, etc. Analyzes should also be made electrophysiological of these cells before implantation, for example using micro-electrodes intracellular to check refractory areas and potentials action and of membrane and control their motor capacity for example by the measuring the deformations of their elastic matrix. These prepared cells for their contractile function can also be used in case of FA to form a implantable myocardial tissue in the atria, achievable, for example, through a catheterized vein, under control at least echocardiographic, the probe or probes can also pierce the septum auricular to seed also the left atrium; this seed 3o subendocardial clusters of these implanted myocardial cells either one, either bridging between rootings with care to avoid a perforation of the wall as well as a detachable protrusion in the atrial cavity, this can be done by an orientable catheter provided with its end of a cylinder containing a narrow retractable spout of the pointed catheter and soft sliding on the endocardium lifting by suction the endocardium and the spitting very lightly at this point by pushing a cylinder of cells to implant (CLI) in the small crack obtained using a piston that is full in thrust and which is recoiled attached to the walls of the catheter for example in the form of an elastic lip valve driven by pressure or Using an inflatable and deflatable balloon capable of cutting the CLI, the recoil or deflation causing a new "cylinder" of cells, adjustable length from the outside, in front of the piston or balloon in the catheter by pressure of a fluid (Fig. 4). Clusters and cell bridges implanted (CLI) will expand and form a network with contractile mesh 10 driven by a STIO or simple stimulation, for example located in the right atrium and the CLI should, by proximity effect, merge in the syncytium and induce certain parts of their equipment genetic. Such a cell implantation catheter can be applied to any region of the heart and other organs such as kidneys, pancreas, liver etc. This The principle of implantation of autologous cells multiplied multiply easily and prepared for a contractile function can also apply to the construction of a total or partial artificial heart constituted at least partially by cultured autologous cells, preferably from partially dedifferentiated myocardial cells.
In a preferred embodiment of the invention, cloning is carried out partial cell therapy that involves introducing into an oocyte denucleate a total or partial foreign nucleus and remove this material nuclear at a desired stage of his mitosis and then implant it in a cell of autologous preference, differentiated pitted or not, in which will end the first mitosis leading to a dedifferentiation partial.
It is thus possible to envisage a purely nuclear partial cloning of removing the selected and unfinished mitotic cell nucleus of the oocyte before the first full cell division, at a time determined, for example by optical analysis, of the evolution of the nucleus. So, for example, during prometaphase, if a light dedifferentiation is desired, or during anaphase or telophase, if further differentiation strong is desired. Then we will introduce it into a cell membrane living preferably emptied of its nucleus, preferably autologous, embryonic or stem cells eg dermal, epithelial, lymphatic, conjunctive, bony, cartilaginous, sanguineous or muscular.
These cells can then be introduced as a result of incomplete cloning.
in a myocardial cell where she will be able to exercise a transcription and regenerative gene expression capable of inducing at least locally and temporarily, in its environment, an action and contamination partial genetics of a desired degree.
It is also possible, in a variant of the invention, to introduce into the oocyte a nucleus already found, spontaneously or by provocation 1 known artificial, in uncompleted mitosis even in mitosis completed, under shape of the first two cells, in order to more easily partial dedifferentiation.
Given the scarcity of human oocytes or mammals, plans to return a multiparous oocyte by introducing a new nucleus after delicately removing the first partially mitotic nucleus.
This multiparity by consecutive intra-oocyte inoculation can have on the nuclear material a dedifferentiation effect different from that obtained then of the first introduction of the nucleus or chromosomes or genes of this same oocyte.
2 o It is also possible to introduce into the oocyte a nucleus, which is already in spontaneous or partially induced mitosis, or otherwise chromosomes or genes or part of nuclei to be treated in a cell of type embryonic. This one will preferably be of the same fabric, for example myocardial, preferably partially denatured and culturable in vitro, vivo or in situ. This or these cells will be cultivated for multiplication of preferably sufficient time in vivo in embryonic tissues to obtain partial dedifferentiation. The nuclei thus treated can be left, either in embryonic-like cells to form a tissue grafted into the kernel's source organism, either extracted from their 3 o host cells to become cell regeneration inducer local at the level of a differentiated tissue, preferably autologous and identical.
The implantation of the nucleus or nuclear parts can also be done at within a stem cell, preferably of the embryonic type or fetal.
Such partially and selectively dedifferentiated cells can then be introduced into myocardial cells, original preference, in survival, preferably more or less pitted and serve as regenerative myocardial tissue for implantation, for example, in areas ossified by fibrosis, poorly vascularized, or insufficient contractility of the heart.
From a certain degree of dedifferentiation, these cells lose their immunogenicity and can be used to regenerate tissues non-autologous myocardial This function also includes the capacity of these cells genetically activated to act remotely by secretion, release or Induction, especially by specific biochemical molecules. This trans-humoral genetic activation shows, among other things, the ability to mobilize pro-generating cells of local appearance as they are observed in extensive myocardial infarction.
This cell preparation, also applicable to other types cells, can create controlled regeneration tissues to treat many organic and tissue lesions. So, for example, by taking, under ultrasound control, a trans-rectal prostatic cells that will be totally or partially cloned and reinjecting the same way into the prostate, this cellular rejuvenation inducer may, in some cases, oppose the development of cancer local or curb its extension. So too, an autologous ophthalmic retina, even homologous, regenerated may be of great interest in case of AMD, and severe renal failure can be prevented by implantation of partially dedifferentiated cells obtained, after transfer into then out of oocytes, nuclei of different nephron cells, and osteoarthritis relieved by implantation of chondrocytes from partial cloning;
he the same goes for cutaneous surfaces and especially to regenerate normal hair, for example by transferring into the oocyte one or more nuclei or parts of hair follicle cell nuclei and / or melanocyte, for a regeneration of the hair and / or its color.
An important application of the invention is to strengthen or recreate thymic functions by genetic rejuvenation of cells homologous or, if possible, autologous identified to actively resuscitate the immuno-protective functions of the 3 5 bodies.

In case of atrial fibrillation, a main application of the invention consists in transplanting these partially dedifferentiated cells and functionally driven to synchronized contraction in the laboratory in implanting them, for example, into layers or grids in contact with the myocardium auricular where they can gradually multiply and / or grow and / or genetically modify the diseased cells of the atrial myocardium, and / or also act by secretion activity and humoral induction, biochemical, mechanical or physical, can be by intervening in a field morphogenetic.
In an advantageous embodiment, it is excised under microscope a myocardial cell and we keep the membrane and the cytoplasm living in culture after extracting one, several or all nuclei. This or these extracted nuclei will be introduced in isolation or in groups in an oocyte or several oocytes, preferably beforehand enucleated, and we will wait, preferably by observation under a microscope, only the pro-, meta-, ana-, or telephase before taking them and reintroduce into the membrane and the cytoplasm preserved alive or culture or in another myocardial syncytial cell, preferably emptied of some or all of its nuclei.
2 o These cells with more or less dedifferentiated nuclei will be put in appropriate culture and multiplied, preferably on elastic stakes biodegradable, for example a collagen matrix or an elastic textile biodegradable in vivo, and preferably stimulated gradually by orthorhythmic pacemaker simple or inotropic in order to adapt physiologically to their future insertion either in the sick myocardium or senile of the patient, either to constitute the auto-contractile walls of a heart artificial partial or total, and subsequently implanted in the patient, especially also at the atrial level to suppress a fibrillation auricular, especially also to form segments of coronary arteries 3o active and contractile used as conductive coronary stents and physiological thrusters, this coronary contractility and distensibility active and additional passive which may be provoked by a electrical arterial stimulation of arterial smooth muscle shifted into diastole versus ventricular contraction, or form a coronary artery almost whole or extra, for example, may come from a dedifferentiation or partial cloning of autologous arterial cells muscle and also coronary endothelial restoring an artery autologous coronary rejuvenated functioning on possibly tutors elastic or extensible, absorbable or not.
In a variant of the invention, a selected part is introduced a chromosome or an entire chromosome or gene in an oocyte functional, either singly or accompanied by a part of the nucleus or differentiated cell nucleus, preferably original autologous or not of origin, partial or whole to treat. These cores to be treated can hearth 1o selectively deprived of the diseased chromosome or chromosomes replace in order to make the nucleus tolerate its chromosomal reconstitution selective and / or partial dedifferentiation gene.
Of course, we can substitute for the part of chromosomes or whole chromosomes to dedifferentiate one or a group of genes without for to cross the field of the invention.
It is thus possible to transplant one or more groups of genes into a oocyte adapted, whether or not there is a selected group of chromosomes or at least one cell nucleus whose dedifferentiation selective and partial, for example in metaphase or anaphase, will allow remote optical microscopic observation, to precisely monitor the chromosomal reorganizations of the preparation of cell division allowing the isolation of chromosomes and the selective destruction of one or chromosomes or chromosomal regions, for example by laser radiation, in a manner known per se, and their replacement by a or corresponding chromosomes or healthy regions, and to submit then the nucleus thus modified to a partial dedifferentiation in a oocyte.
Extraction of partially dedifferentiated nuclei or chromosomes can be done, for example, by intra-oocyte injection of a suitable serum 3o under slight pressure after sufficiently mobilizing the material nuclear with a micro-rod or paddle or by the vibratory action of ultrasound or laser.
It will be easy to verify by the degree of nuclear integration or peri-nuclear, this integration being optically visible.

In case of creation of chromosomes or artificial genes whole or partial or artificially induced, it is often appropriate to submit these elements to such a partial dedifferentiation in order to create them a past genetic evolution without which their future may be compromised. When 5 these artificial elements with genetic function do not support any involution dedifferentiation gene, their future functionality is uncertain.
Tissue transplants require for their success elimination sufficient lymphocyte reactions from serious discharges usually from antigen, antibody and humoral type of the recipient organ as observed 10 in the pregnant woman who biologically tolerates, through her placenta, his fetus. It is appropriate, for example, to imitate genetically and / or plasmatically these tolerance characteristics, in particular lymphocytes and thymus functions. In the adult human being and especially elderly, the presence of cells and functions of the thymus is often too 15 weak or absent. It may be useful, for example, to transplant a fabric of homologous thymus, partially and selectively dedifferentiated and genetically adapted, for example, by chromosomal integration selective chromosome graft in cell nuclei of the recipient organism and this is by genetic preparation of cells 2 o blood strains of the recipient organism either by preparation in culture cellular in vitro or in vivo (such as sub- or intradermal) with or without hyper-expression of their telomerase or Sir2 protein to prolong their life and to induce their antigen and antibody-induced addiction critical to the cells to be grafted by known means of the induced influence to 25 by biochemical and hormonal substances on the expressions of certain genes.
Such cells genetically adapted to different tissues recipients are particularly useful for the radical cure of fibrillation atrial as well as for retinal regeneration, implantations of 3o pancreatic tissue without protective membrane, nephron regenerating, intra-cerebral dopaminergic cells against disease Parkinson's, dermal and epidermal regenerative tissues, including hair, prostate tissue or mammary glands for the treatment of corresponding cancers, and in particular thymus Regeneration and any other functioning cells or indispensable especially tubes and digestive systems, nervous, dermal, respiratory, skeletal and cardiovascular.
Coronary arterial, carotid, renal, etc., lesions may be deadly and ideally require radical regeneration treatment tissue and functional. For this purpose, the invention comprises a variant able to collect autologous arterial muscle cells or homologues and subject them to a controlled partial dedifferentiation according to the above methods. These cells can then be grown arterial or in vitro around a guard preferably elastic, dissolvable or not, in the form of a tube and in a serum circulating intra-tube under pressure pulsatile gradually increasing to recreate the contractile function and of elastic relaxation of the cells in order to reconstitute an arterial desired diameter. Arterial endothelial cells will likewise be cultivated partially dedifferentiated as a tube of smaller diameter than it will be introduced at the end into the largest tube thus grown. Such segments partially dedifferentiated and tolerated arterial then either replace diseased arterial segments or parallel or in addition to a faulty network.
At the level of the coronary arteries, one can thus create, for example, 2 o living and self-contractile "stents", implantable for example by endo-arterial catheterization. Current stents are made of a material plastic or metallic inert and immobile and replace an arterial segment more or less self-contractile but thrombosed, contributing to the desertification of small arteries and coronary capillaries downstream. These stents Artificial not only have no active action such as propulsion blood coordinated with the local motor arterial wave but still disrupt the normal flow dynamics of the entire artery concerned, often resulting in the desertification of small vessels downstream of the stents.
On the other hand, a reconstructed physiological coronary artery segment, autologous, living, actively pulsating by strengthening the arterial need genetically "rejuvenated" by partial dedifferentiation not causing no rejection reactions of the recipient organism of the transplant, can reconstruct a very active physiological arterial segment that can be able, in addition, to improve the blood circulation of the whole artery, by example by its mechanical capacity (soliciting the mechanical sensitivity of certain genetic expressions) and by secretions and genetic induction of factors that can cause some cellular rejuvenation at a distance.
Normally, this "pulsatile physiological stent" will be activated spontaneously, especially by variations in wall pressure and blood. If necessary, the coordinated rhythmic activity of this segment of "Physiological stent" may be provided by an electronic pacemaker arterial pattern adapted to the rhythm of the arterial beat, for example by a detector ventricular or intramyocardial intracavitary pressures and / or the ECG
lo and stimulant in diastole, for example, also in relation to the rhythm of cardiac pacemaker.
One can also place on such an arterial stent, preferably towards his distal end, a sensor of pressures, oxygen saturation and ECG, during in vitro tissue reconstruction, these sensors being totally surrounded by living tissue, and connect the leads, of cardiac pacemaker or implanted defibrillator, which allows to know continuously the effective local blood circulation without perform a momentary fluoroscopy with injection of contrast.
2 o In order to preserve the needs of an intervention without delay of a stent placement, it is necessary to implant an emergency stent immobile which is gradually dissolvable or removable or infiltrable by the <e stent physiological coronary reactivation by catheterization.
In a preferred variant of the invention, this arterial segment reconstituted coronary is provided, in living continuity, with arteries, arterioles, capillary and venous networks with their irrigated myocardial tissues; this functional tissue block being previously cultured and multiplied in vitro Yes N
vivo, preferably from autologous cells, partially dedifferentiated, adequate venous stopping of this tissue being planned to the ventricular cavity or the coronary venous sinus. This block restored myocardium will be able to progressively induce a recolonization of capillaries and small coronary arteries of the myocardium original.
Implantation of a physiological stent by arterial catheterization classic will work initially by arterial blood supply imbibition, as carried out during its cultivation, from the endo-artery.
Gradually, the great vitality of the renovated physiological stent will create new vaso-vasorum. Subsequently, the dominant vitality of this arterial segment will produce some enlargement of the caliber of this stent according to his metabolic needs.
A further application of the invention is to reconstitute gradually in vitro, preferably after partial dedifferentiation of first cells of different heart tissues and their multiplication 1 o beginner, part of ventricle, for example in case of aneurysm or ventricular necrosis, or the set of two ventricles, using extensible or somewhat flexible or biodegradable stakes and adequate growth and respecting the ventricular geometry in three dimensions ensuring vascular connections as can be obtained at from a three-dimensional echocardiography (N. Mirochnik, A.
Hagège, F. Zacouto and C. Guérot: Arch. Wrong. Court, Paris, 93, October 10 2000).
In other variants, the invention can be applied to grafts cells and tissues without serious rejection reactions, through the use of of Partial and / or selective cloning.
In a variant of the invention, a selected part is introduced of a chromosome or an entire chromosome in a functional oocyte suitable either singly or in combination with one or two nuclei Cellular, preferably autologous to the recipient or not of origin, partial 25 or whole to be treated. These kernels to be treated can be private selectively from or diseased chromosomes particularly isolable during a phase of their mitosis that it's about to replace with chromosomes equivalent to preference of embryonic or genetically partial types dedifferentiated in order to make the nucleus tolerate its reconstitution Chromosome genetic selective and / or partial dedifferentiation.
Of course, we can substitute for the part of chromosomes or whole chromosomes to dedifferentiate one or a group of genes without for to cross the field of the invention.
It is thus possible to transplant one or more groups of genes into a Adapted oocyte, with or without a selected set of chromosomes or at least one cell nucleus whose dedifferentiation selective and partial, for example in metaphase or anaphase, will allow remote optical microscopic observation, to precisely monitor the chromosomal reorganizations of preparation for cell division to using the movements and appearances of the intracellular elements or centriolar nuclear energy, the beginning of the formation of a nuclear membrane, movements and densification of chromosomes, etc. In other words, it is a question of dedifferentiating sufficiently either groups of genes or previously selected chromosomes and then transplant them into an oocyte carrying the nucleus to be genetically modified and previously devoid of the affected chromosome or chromosomes.
A variant of the invention consists in partially co-dedifferentiating in a single or autologous oocyte denucleated to induce a tolerance reciprocal immunity between, on the one hand, a cell nucleus of which one or several chromosomes or parts of diseased or senile chromosomes have been destroyed during its mitosis and, on the other hand, one or more parts of chromosomes or whole healthy chromosomes, preferably homologous, healthy and younger. Such cells genetically repaired and dedifferentiated can also be overexpressed by their telomerase Or Sir2 protein.
Extraction of partially dedifferentiated nuclei or chromosomes can be done, for example, by intra-oocyte injection of a suitable serum under light pressure after sufficient mobilization of nuclear material with a micro-stem or paddle and / or the application of ultrasound and / or lasers 2 5 rooms with vibratory effect.
We can easily check the degree of nuclear integration, this integration being optically visible.
In case of creation of chromosomes or artificial genes whole or partial or artificially induced or arranged, it is often necessary to 3o submit these elements to such partial dedifferentiation in order to create a past of genetic evolution without which a future perhaps compromise. When these artificially or artificially combined elements, genetic function, do not support any past by dedifferentiation targeted genetics, their future functionality is uncertain.

An example of starting the process may be to acquire hemodynamics and possibly oxygen consumption corresponding and then determine the coupling intervals of the paired stimulation, either with respect to the ECG R-wave in ms, or by report 5 at the RR interval as a percentage of the previous cycle time, either a an algorithmic combination of the two. We send a train of impulses for, at least one cycle. We acquire the hemodynamics for a cycle and we compared to spontaneous hemodynamics by verifying that the increase obtained exceeds a programmed percentage, for example 20%. If we 10 reaches desired values of hemodynamics and possibly oxygen consumption, we continue this STIO and we continue the acquisition hemodynamics and preferentially oxygen consumption myocardial. If we do not reach the programmed values, we modify, at least, a parameter of the pulse trains and we redo the controls. Yes, 15 after the programmed successive changes of the parameters of the trains pulses, we do not get the desired values, we stop the STIO.
By way of example, FIG. 5 shows a synoptic view of an implanted device according to the invention.
The technical realization of the different hardware components or logical will not be detailed further, whether it is the means of detection or stimulation, sources of energy, and means of logical processing and memory, which are all now quite classic and well known in implanted stimulators.
The device comprises detection and stimulation means 1. For example, sensing electrodes that may also be used for stimulation, as is often the case. of the detection means feed signals of the acquisition means of electrocardiogram 2. These acquisition means make it possible to obtain 3 o in particular, and to memorize, in logical means 3, the rhythm heart rate, ie the RR intervals of the generating waves of the muscle contractions and R-R ', i.e., the interval between the R wave and a coupled R 'wave caused according to the invention at the end of the period refractory (K. Theisen, F. Zacouto, M. Grohmann, H. Jahrmêrker 3 5 Refraktérzeitmessung bei absoluter Arrythmie mit orthorythmischer Serenestimulation, Klin. Wochenschr., 52, 1082-1084 (1974), Springer-Verlag). These means also make it possible to determine which pulses of the pulse burst that caused the R 'wave.
It is thus possible to obtain in 4 the determination of the period refractory.
The device also comprises means for detecting hemodynamics 5, such as an intracardiac pressure sensor or intramyocardial and volume sensors by measuring impedance, and means measuring the kinetic energy of each expelled volume (by 1 o example by measuring the slope ~ p / Ot of pressure variations and / or volume, again by implanted Doppler sensors or accelerometers), these means making it possible, in means 6, to acquire these data the calculation of the hemodynamic performance, ie the volume of blood ejected and, in relation to the rhythm, cardiac output. Of Preferably, the hemodynamic sensors 5 comprise a sensor of intramyocardial pressure located near an intraventricular electrode of detection and stimulation being part of the means 1. The means 6 are responsive to the magnitude of the pressure detected by the pressure sensor, and verify whether this amplitude varies soon after the pressure buildup, for determine the ZMRR area. Values from means 6 are addressed to comparison means 7 in which we also memorized is a threshold above which we would like to maintain hemodynamics, a haemodynamic optimum that would have been recorded, for example previously, by the device according to the invention. These means 7 address the result of their calculation to means 8 which also receive information on the refractory period from means 4 and the characteristics of the electrocardiogram, especially the rhythm from the means 3. In the logic means 8, the coupling, that is to say, the interval that is expected between the last wave R
who 3o has just been detected and sending the stimulation or salvo impulse stimulation, these means may also, where appropriate, modify, in function of the information received, not only the coupling interval if there takes place, but also other characteristics, such as the duration of the burst, the number of pulses, the interval between pulses or even the intensity or duration of each pulse.

Means 8 control means 9 for generating a salvo pulse.
The comparison means 7, depending on the degree of effectiveness of the observed hemodynamics and its comparison with values may still possibly change the frequency of stimulations by means 10 driving the pulse generator 9, by example, in the case where the spontaneous electrogenesis of the patient is insufficient to cause a proper heart rhythm.
The device may further include metabolic sensors 11, 10 for example local oxygen saturation pressure or its equivalent in transmembrane or free electron concentration as measurable by an oxidation-reduction coefficient inside a sinus vein coronary artery and, for example, relating to the right intra-auricular venous blood and left intra-atrial arterial and / or CO2, and / or pH sensors etc.
connected to acquisition means 12 determining a value, such as the 02 consumption acquired for a comparison in means 13 with one or more thresholds programmed or previously stored. We can, thus, implementing a logic means 14 which influences the means 10 (or in a simpler case, on the means 8) to modify if necessary the 2 o parameters or the coupling of the salvo, or other variations provided for in the means 10.
The device represented in FIG. 6 presents the means identical to that described for claim 5, and means additional. Thus the means 6 is arranged to be able to identify the ZRMM zones in time and geometric position relative to ZR zones and ZNR.
Means of comparison with optimum series already memories can be arranged to memorize critical sequences have already existed or entered by programming and allow an action in case of detection of a sequence of cycles that is estimated critical, for example to act on a means of defibrillation or for stop the operation of the device according to the invention and to make it work at the way of a classical orthorhythmic pacemaker or WI or DDD.

The means 3 is also arranged to also acquire the RR 'intervals directly.
Finally, an additional means 15 is arranged to receive information from means 4, the latter being arranged to acquire information also on arrhythmias, said means allowing thus the detection and selection of arrhythmias, preferably the distinction between the spontaneous arrhythmias and those induced by the device, said means 15 retroactively on the means 10, which controls the sending of the pulses.
1o In echocardiography, STIO allows rest to be done immediately follow to a basal CC one or more CCs with contractility maximum or vice versa and measure their quantitative difference and geometric. For a progressive effort test, however, it will be necessary use conventional means. The comparison between maximum contractility STIO and that obtained by physical effort or substances of the type Dopamine, noradrenaline, etc., may provide new indications myocardial function.
Automatic measurement of the variations of ZRE refractory zones and ZRM during stress tests, especially under control 2o echocardiographic, will allow to know an intra myocardial state cellular.
In case of bi-ventricular resynchronization cardiac stimulation used, for example, in the case of a left branch block, severe hypertrophy of the myocardium, etc. we can, in principle, improve further the hemodynamic result by adding a STIO driven by the stimulator bi-ventricular that will reinforce the intrinsic contractility of each ventricle and lead to a genetic regeneration that is observed at the level of myocardes subjected to prolonged intensive physical training with peripheral muscle exercises.
3o An automatic STIO according to the invention comprises a device to ensure optimal hemodynamics within adjustable for example of rhythm, pressures: max., min., differential, of dimensional variations of the contraction, local and general saturation of oxygen (preferably in the coronary sinus and arterial blood and venous), regular STIO continuity, etc. In order to realize this for example, a display (Fig. 3) specially programmed at a multi-channel oscilloscope simultaneous and using known signal processing and algorithms, which includes for example, in real time, the following parameters a) an ECG trace showing 3 to 5 fast-running cycles, (b) the marking of spots (spikes) of detections and stimulations at electrode level on a line, c) a tracing showing the intra-cardiac ECG, preferably in monopolar, for example on a tri-polar probe, the stimulation being lo in bi-polar, which makes it possible to determine which of the impulses of a salvo actually drives the propagated electrical depolarization allowing thus the automatic measurement of the ZRE and their variations at each CC, measures made possible by the orthorhythmic pacemaker, even in case atrial fibrillation (K. Theissen, F. Zacouto, Klin Wschr 52, 1082-1048, 1974, Germany, Springer-Verlag), d) a plot showing the mechanical curves, variations of pressures, volumes and acceleration, e) a plot showing oxygen consumption or equivalent if possible for each or a few cycles, such as, for example, saturations of venous and arterial coronary oxygen and their difference and / or local oxidation-reduction coefficient arteriovenous, etc., which can alert preventively before any hypoxia of overconsumption of oxygen from myocardium, which manifests itself first of all by an accumulation of extra-membrane of electrons.
The STIO stimulation device can be associated with all categories of implantable DIA automatic pacemakers, and also, in particular, automatic defibrillators, anti-tachycardic, WI, DDD, DDDR, etc.
By way of example, reference is made to FIGS. 7 to 9.
In this example, the practitioner or the device according to the invention a patient suffering from significant heart failure has a spontaneous spontaneous heart rate, for example, less than 125 p / min, and for example preferably less than 100 p / min.
Line 1 of FIG. 7 shows the regular rhythm of the R waves ( QRS complexes) of this patient, ZRE representing the refractory zone electric, determined, for example, by one of the means described in the present invention.
Line 2 represents the mechanogram detected in response. On this curve, the mechanical refractory period ZRM, and 5 that the mechanical diastole D.
Line 3 shows the electrocardiographic simulation an isotropic stimulation according to the invention, in which one sends a salvo coupled immediately, at the time of the end of the electric refractory zone ZRE and we see the extension of the refractory zone that follows the complex R ' 1 o caused by simulated coupled stimulation. In this simulation, the means of computer processing the device have provided that the pace of base is hardly altered by simulated inotropic stimulation and complex spontaneous R occur therefore as they would in the absence of stimulation.
Line 4 shows the estimated increase in duration and intensity of the mechanogram, an increase which is immediately apparent from the second spontaneous R wave, that is to say the first that follows the inotropic stimulation R '.
This results in a decrease in the diastolic duration 2 o Mechanical D ', which is less than D.
We then proceed to the real inotropic stimulation of the heart as provided in simulation curve 2 of Figure 7, and it is verified that immediately gets an increase in hemodynamic performance from the first consecutive cycle, as on line 4. We continue to 25 this verification for a certain period of time or a certain number of cycles cardiac, for example corresponding to one or more tens or one hundred cycles, it being understood that one should normally obtain, after the immediate increase in performance in the second cycle, a incremental, additional increase spanning tens or 3 o hundred consecutive cycles.
One can also simulate in the same patient, the effect that would obtain the inotropic stimulation according to the invention, based on the faster rhythm imposed by stimulation pulses R3 which prevent the occurrence of spontaneous signals R (R2 is represented by the QRS complexes removed). On line 5, we see the electrocardiogram corresponding to this simulation with burst coupling and electrical capture of the heart.
Line 6 represents the estimated increase in the mechanogram per this simulation. Thanks to means of comparison of the device, it is possible then compare the effects of the simulations along lines 2 and 6, and, by example, in the case where it is estimated that the increase in performance hemodynamics from single coupled stimulation along line 3 is insufficient, we can propose the implementation of a stimulation according to line 5 if the increase and the expected mode is higher and allows to achieve an acceptable increase in cardiac performance, by example a doubling compared to spontaneous cardiac output such than estimated on line 2.
Once the simulation has been chosen, the device proceeds effectively to an inotropic stimulation along line 3 as described above or according to line 5, depending on the choice made, and the means of acquisition of hemodynamics and / or oxygen consumption allow to verify the existence and the extent of the increase in hemodynamic performance and compare it to the simulated increase.
In the absence of increased hemodynamic performance, for example during the first two cycles of coupled stimulation or paired, the device stops the inotropic stimulation.
On the contrary, if a hemodynamic increase is observed, the stimulation continues, preferably over several tens, or one or several hundred cycles. We then compare the performance hemodynamics obtained to that resulting from the simulation. If the performance obtained is comparable to the targeted performance, for example in a range of 15% of the targeted performance, we continue the stimulation inotropic. If the increase in performance achieved largely exceeds the simulated increase, the device can eventually decrease the performance, for example taking into account a stress index CSI cardiac and comparing CPI performance indexes and stress CSI, as described in US Patent 5213098 incorporated herein by reference, and it may be possible to perform the inotropic simulation only for a reduced proportion of cycles. If on the contrary, the performance observed is much lower than that estimated as necessary and expected by the simulation, the device can stop the inotropic simulation.
Referring to FIG. 8, there is shown a case of insufficiency associated with a spontaneous rhythm tachycardia, for example higher at 125 cycles per minute. The last spontaneous cycle R is shown than on line 2, the corresponding hemodynamic performance.
In such a case, the device simulates sending a stimulus burst towards the end of the refractory period of the last spontaneous signal R, which prolongs the refractory period of the heart, so that the QRS complex 1o, which would have occurred at the moment R2 because of tachycardia, can no longer occur, which causes the occurrence of a spontaneous complex R3 delayed. The coupling stimulus burst R4 is then continued and we see that each time preventing the occurrence of the complex spontaneous tachycardia R2, we obtain, finally, a lower rhythm, by example divided by 2.
Most often, however, it is preferred to provide care complete electric heart; the spontaneous complex R3 is then replaced by stimulation at a slightly faster pace.
At this normal stabilized rhythm, normally corresponds a 2 o increased simulated haemodynamic performance because the EPR effect (PESP) overcompensates greatly the decrease in the number of contractions per minute.
If this simulation makes it possible to expect hemodynamic performance sufficient, the actual inotropic stimulation is actually to the procedure of line 1 of Figure 8, and as previously stated we check the response and the amplitude of the response obtained during one, two or three cycles and then for a higher number of cycles. In such a realization, one can also, in case the hemodynamic performance simulated and / or actually obtained would not be sufficient, proceed to a stimulation pulse at a higher rate.
In FIG. 9, the electrocardiogram and the corresponding mechanogram of a patient. The electrocardiogram represented on line 1 shows QRS complexes and more precisely the spontaneous R wave or stimulated at a basic rate, for example 60 beats / min. The appearance of the QRS complex creates a refractory zone electrical ZRE that ends more or less with the T wave, without a sufficient correlation can be generally established. This zone refractory is followed by the electrically sensitive diastole DEL.
On line 2, we see that the pressure rise of the mechanogram takes place after an electromechanical coupling delay EM, also called E
thereafter. At first an isovolumetric contraction occurs as long as the valves are not open, for the duration CI. This contraction is followed of a contraction with EJ blood ejection between the opening A of the valve aortic and M opening of the mitral valve. DE represents the diastole 1o mechanical, first motor, then elastic and passive filling.
The maximum mechanical refractory zone, during which the muscle heart is in the most contracted state, is represented by ZRMM. This area, which corresponds to the top of the pressure curve, is, in the example shown, relatively flattened because the pressure curve has been obtained by a sensor measuring the intracavitary blood pressure in the ventricle. However, when placing a pressure sensor Intramyocardial in a region or local area, the rise in pressure local is very clear and makes it easy to distinguish the area refractory local maximum mechanical close to the active electrode.
In one embodiment of the present invention, one acquires the electrocardiogram of line 1 in this local area, for example from preferably the myocardial region adjacent to the ventricular electrode of stimulation and detection, and one acquires the pressure curve intramyocardial also in this myocardial region. We reason in the following as if the curves of lines 1 and 2 of Figure 9 represented these local curves in the selected region.
It is then observed that the electric refractory zone ZRE can overlap partially or even totally ZRMM area. When the superposition is partial, we define, between the end of the zone ZRE and the end of the 3o ZRMM area, an effective ZCE critical area to target, which may be equal to the ZRMM zone in case the ZRE electrical refractory zone ends before the start of the ZRMM zone, and that can be zero if ZRE is lengthened and includes the duration of the ZRMM zone.
According to the most preferred embodiment of the invention, the coupled or paired stimulation is sent during the ZCE zone. This one can be quite often of the order of 30 to 40 ms and, in this case, the sending, early enough towards the end of ZRE, a burst of impulses having a interval between pulses, for example 20 ms, will cause certainly a stimulation in the targeted ZCE area, without any increase pejorative of local oxygen consumption, stimulation that will produce the post-extra-systolic reinforcement expected with the smallest increase of oxygen consumption, compared to the increase in work Mechanical myocardium RPE (PEPS).
If the ZCE zone tends to shrink, the device can then 1o advantageously decrease the interval between the pulses of the burst of to ensure that a burst pulse will fall into this ZCE zone.
However, it is preferable not to shorten the duration between two pulses consecutive significantly below 10 ms, the electronic means not allowing, in this case, to identify the stimulating impulse of the burst.
Therefore, it is preferred if the ZCE zone is less than 10 or 15 ms, do not send paired or coupled pulses.
It will be the same if we observe a number of cycles that the ZCE zone varies too anarchically in duration or in time.
In a particularly advantageous embodiment, will detect the ZRE zone by the use of pulse trains as this has has been described further, and we will memorize the positions and durations of the zones ZCE of a plurality of cycles, for example from 30 to 3000 cycles, for detect whether the ZCE zone is approximately stable or has a downward or upward trend and we will then be able to intervene in Consequently, this time by sending a stimulation pulse, preferably towards the estimated end of the ZRMM zone of the current cycle, in assuming that the ZCE zone will exist at this time.
We will thus be able, thanks to these memorizations and verifications which will be able performed by the simulator SIMA analyzer according to the invention, to make 3o so that only a small number and even no impulse ensuring a electrical depolarization does not occur outside the ZRMM zone, allowing to limit the local oxygen consumption caused by paired or inotropic coupled stimulation. Choosing appropriately in the heart the place where one detects intramyocardial pressure and the electrical depolarization and stimulating in or near this place, we can make sure that the intramyocardial spread of the depolarization, caused by the inotropic stimulation, is done in concordance with the persistent spread of a strong contraction, and including maximal myocardial contraction in the new 5 territories where the stimulation depolarization spreads, so that the Oxygen consumption resulting from paired or coupled stimulation will also remain limited in much, if not all, of the ventricular myocardium. For this, we prefer to detect the zone ZRMM in an initial myocardial zone where the spread of depolarization begins, 10 the electrical impulse then propagating in the rest of the myocardium at the same time time and at substantially equal speed as the maximum contraction, their coupling remaining sufficiently constant.
In some special cases, for example, if it has been possible to detect a modification of the functioning of the intramyocardial beams of Conduction, for example in case of branch blocks or local areas pathological, we can detect the ZRMM zone and possibly the corresponding electrical depolarization signals in several places and stimulate in these places during their ZRMM zones or more precisely ZCE respective.
FIG. 10 shows the increase in efficiency haemodynamic simulated on three spontaneous cycles in a patient.
Line 1 represents the spontaneous rhythm for example of 90 p / mm in an acute heart failure.
Line 2 represents the variation of spontaneous pressure in the left ventricle generated by the spontaneous rhythm.
Line 3 represents the electrogram of a simulated paired stimulation in this same patient, who maintains a rhythm identical or similar to that from line 1.
Line 4 represents the simulated variation in left ventricular that results.
Line 5 consists of a superposition of pressure differences Line 2 and Simulated Line 4, the differences being hatched.
In particular, it can be seen that the initial pressure rise slope ~ p / Ot systemic increases by 25% and the diastolic ~ p / Ot slope, that is to say pressure decrease of more than 30%.
The flow per systole is increased by 35% and the flow per minute of 33%.
The duration E of electromechanical coupling is reduced by 30%.
The analysis of this simulation shows a significant increase in hemodynamics.
In FIG. 11, there is shown the control panel of a SIMA device according to the invention, divided into three parts 101, 102, 103.
1o The panel 101 has an atrial control sub-panel 104 corresponding to stimulation electrodes and atrial detection and a ventricular sub-panel 105 corresponding to electrodes of stimulation and ventricular sensing. Panel 104 shows three setting buttons, namely 108 to choose the amplitude of the pulses of stimulation, 109 for the detection sensitivity and 110 for the duration between the atrial and ventricular pacing if DDD mode is selected. The ventricular panel 105 has three buttons 111, 112, 113 for the adjustment and amplitude of ventricular impulses, sensitivity of the ventricular sensing electrode and the atrioventricular offset.
The 2 o button 114 to set the pace of orthorhythmic stimulation. The button 106 makes it possible to implement or interrupt the stimulation and the button 107 to switch to atrial, ventricular or DDD mode.
Panel 102 has pacing control buttons STIO according to the invention. The button 115 makes it possible to implement or to interrupt the stimulation STIO and the button 116 can not trigger automatic stimulation only for one cycle.
The sub-panel 117 has a set of buttons, namely 118 for the coupling (in percentage), 119 for the coupling in ms. fixed, 120 to display the period of basic stimulation.
The sub-panel 121 allows to choose the proportion of cycles to stimulate.
The sub-panel 124 has three buttons 125, 126 and 127 to define the pulse parameters of the pulse burst inotropic stimulation, ie the number of pulses in the burst by the button 125, the interval between the two consecutive pulses in the salvo by the buttons 126, and the amplitude of the pulse of the burst (button 127).
The emergency stop button 128 allows the immediate stop of the inotropic stimulation.
The lower part 103 makes it possible to display and adjust the simulation SIMA according to the invention, and to compare the simulation as well with the parameters initially detected by possibly operating part 101, that parameters derived from the actuation of a STIO by Table 102.
Part 103 includes a screen 128 on which the 10 electric, real mechanical and simulated curves and their juxtaposition, as shown in FIG. 10.
A subpanel 130 displays the spontaneous values detected (spont), simulated corresponding (simu), and their comparisons in percentage of spontaneous value, for the Op / ~ t diastolic parameters, systolic ventricular rate, ventricular rate per minute, and E-value electromechanical coupling of the ventricle.

Claims (138)

1. Device for stimulating and / or strengthening the heart muscle and / or myocardial cells allowing a significant increase in the hemodynamic performance of the heart and / or the treatment of tachycardias, tachyarrhythmias or atrial fibrillations, comprising:
means for automatic acquisition (1,2,3) of the cardiac rhythm, and, optionally, of its origin, making it possible, in particular, to know the interval between at least the last two R waves (caused or spontaneous) of the cardiac cycle that has just ended, means for precise acquisition of cardiac hemodynamics, means (4) for determining, continuously or periodically, in real time, the duration of the electric refractory period (ZRE) following the last R wave of said cycle, means for evaluating at least one parameter relating to the cellular functional state of the myocardium, and means (8, 9, 10) subordinate to said evaluation means to address substantially without delay at the end of said refractory period (ZRE), at least one stimulation pulse, paired or coupled, adapted said cellular functional state. 2. Device according to claim 1, wherein said means assess the position and duration of an effective critical area at target ZCE, which is placed immediately after the end of the refractory zone Electric ZRE, and ends at the end of a contraction refractory zone maximum myocardial ZRMM, sending said stimulation pulse intervening in the said ZCE zone, if it is present and can be targeted. 3. Device according to one of claims 1 and 2, wherein said means of evaluation detect, at each cycle or periodically, the threshold excitability of the myocardium. 4. Device according to one of claims 1 to 3, wherein the means (8,9,10), substantially towards the end of said period Refractory (ZRE), a burst of stimulating impulses, the duration of the salvo and the repetition interval of said pulses being such that a impulse of salvage stimulation is addressed to the heart substantially without delay after the end of the said refractory period. 5. Device according to claim 4, wherein the means (4) of Determination of the duration of the electric refractory period (ZRE) are sensitive immediately to the detection of that of the impulses of a salvo that has triggered a complex (R '). 6. Device according to one of claims 1 to 5 wherein, y included in the case where, instead of a salvo, the device generates a single stimulation pulse, the means (4) for determining the duration of the refractory zone are arranged to acquire by a scan of a second pulse, the substantially exact duration of the refractory zone, this sweep being conducted for example during previous cardiac cycles or in Classes. 7. Device according to one of claims 1 to 5 wherein the beginning the stimulus pulse burst is chosen to start, just before the estimated end of the refractory period, and the duration of that salvo and, by therefore, the number of stimulation pulses is advantageously such that at least one stimulation pulse will intervene before and one following very soon after the end of the refractory period. 8. Device according to one of claims 1 to 6 comprising means to advance or retreat the salvo compared to an estimate of the refractory zone, and / or change the interval between pulses to the interior of the burst, the device having automatic acquisition means, in particular by obtaining the intracardiac ECG to determine, particularly by treatment of the intracardiac electrical signal at the level of the sensing and / or stimulating electrode what is the stimulation pulse in the burst that triggered the R 'wave, and, as a result, eventually change the salvo. 9. Device according to one of claims 1 to 8 comprising means sensitive to spontaneous or stimulated R waves and / or determination of electrical and mechanical refractory zones, in particular by sweeping the whole salvo or just inside that salvo and / or means for very quickly determining the thresholds of excitability of the heart, for example by providing stimulation pulses of variable intensity included infra-liminary to allow their measurement instantly to inside the salvo. 10. Device according to one of claims 1 to 9 comprising means of anti-tachycardic stimulation and means sensitive to extrasystoles to automatically stop said stimulation in case of occurrence of excessive hemodynamic instability or arrhythmia electrical system meeting predetermined criteria. 11. Device according to one of claims 9 and 10 further comprising the rhythm acquisition means, the duration determination means refractory zone and means for sending a single pulse or a burst, means (7, 10) sensitive to the precise acquisition of hemodynamics in relation to the rhythm and its origin in the heart for to determine the variations of effectiveness of the hemodynamics, these means being likely to control the sending and possibly the parameters of the impulse or salvo, preferably at a pace close to that which has produces the most favorable hemodynamics for the patient at a time given. 12. Device according to claim 11 wherein said means act on parameters such as: a programmed ventricular rhythm and / or an automatic adjustment of the beginning or the end or duration of the salvo or the number or characteristics, including width, intensity interval, polarity of the pulses in the salvo, or a location of the sending of the burst on one or between different stimulation electrodes. 13. Device according to claim 12 comprising means for gradually reduce a salvo to a single or a small number impulses, in particular by periodically feeling with at least one second impulse that moves progressively ahead of the impulse stimulant to automatically measure the beginning of the non-refractory zone, so that when the exploratory pulse recedes to the stimulating impulse, the latter may be retracted, in particular periodically in case instability of operation until the beginning of the decline in curve ventricular volume or increase in consumption of oxygen or a corresponding parameter, in particular the secretion membrane of electrons, local pH or ketone bodies, this position corresponding to the exceeding of the end of the mechanical refractory zone at maximum contraction (ZRMM). 14. Device according to one of claims 1 to 13, comprising, in in addition, means (11, 12) for acquiring metabolic parameters, particular local oxygen consumption and / or its equivalents, such as measuring accumulated electron densities, lactic acid, pH or cetonic corpse. 15. Device according to one of claims 9 to 14, comprising means of switching from paired stimulation to coupled stimulation, to say at a fully stimulated rate, said means being sensitive to means of acquisition of the electrocardiogram and / or hemodynamics, and / or myocardial metabolism. 16. Device according to one of claims 1 to 15 allowing early arrhythmias and extrasystoles, including a plurality of electrodes arranged at different locations of the muscle heart and acquisition means responsive to electrical signals appearing on the electrodes or remotely to find, at a stage early, the occurrence of an electrical extrasystole in an area myocardium close to that of the electrodes initially concerned, the means for addressing the stimulation pulses then being made sensitive to such a finding to emit into an electrode near or in a plurality of electrodes, a pulse or a burst of stimulation whose electrical propagation in the myocardium is moving towards the myocardial zone affected by extrasystole, and result in a fusion between the spontaneous and stimulated depolarizations that blocks the spread of extrasystole. 17. Device according to one of claims 1 to 15 for treat isolated arrhythmias and extrasystoles, including one or more electrodes, especially juxta- or extra-cardiac or intracavitary ventricles, especially without exclusive contact with the myocardium, allowing instantaneous detection of an early extrasystole, said device being arranged to trigger, instantaneously, in case of detection of said extrasystole, stimulation by an impulse or by a burst of impulses to from all the stimulating electrodes available, thus creating a fusion complex between propagations of stimulated depolarizations and extrasystolic. 18. Device according to one of claims 1 to 17 comprising means to quickly detect an extrasystole, the means of the device being sensitive to the acquisition of this extrasystole to diminish or even remove, preferably temporarily, the electrical diastolic phases (D), in particular by increasing the rate of stimulation in a heart under electrical control of the device, either by taking control for send a stimulation pulse, at the very beginning of the diastole electric. 19. Device according to one of claims 1 to 18 comprising means for, in case of occurrence of an arrhythmia meeting criteria predetermined, increase the number and / or intensity of the pulses of the salve to enhance the stabilizing effect on cell membranes myocardium. 20. Device according to one of claims 1 to 19 comprising means for, in case of arrhythmia, to decrease the intensity of the pulses of the burst, the device then monitoring whether the arrhythmia continues. 21. Device according to one of claims 1 to 20, arranged for acquire a cardiac mechanogram, especially until the occurrence of a cycle long enough to get a good myocardial contraction, the stimulating means being arranged to then send an impulse or a salve of stimulation that during the peak of mechanical contraction (ZRMM) located inside the plateau of the mechanogram curve, especially a little before the end of the electric refractory zone (ZRE) after what the device stimulates immediately after the end of the refractory zone electrical power that has just been extended, thus canceling the electric diastole. 22. Device for stimulating and / or strengthening the heart muscle and / or myocardial cells allowing a significant increase in the hemodynamic performance of the heart and / or the treatment of tachycardias, tachyarrhythmias or atrial fibrillations, comprising:
means for precise acquisition of cardiac hemodynamics (5, 6) and comprising means for instantaneous detection of the refractory zone maximal myocardial ZRMM in a precise location of the myocardium, and means for addressing at least one stimulation pulse and, preferably, a burst of stimulation pulses from the region in which the occurrence of the ZRMM zone is detected. 23. Device according to claim 22, comprising means automatic acquisition (1, 2, 3) of the heart rhythm and optionally origin, in particular to know the interval between at least the last two R waves (induced or spontaneous) of the cardiac cycle which has just been completed, and means (4) for determining continuously in real time the duration of the electric refractory period (ZRE) following the last wave (R) of a cardiac cycle, said device being arranged to detect whether an electrical depolarization signal has been well produced by said stimulation in said ZRMM zone. 24. Device according to one of claims 22 and 23, comprising means for detecting and storing the duration of said area maximum myocardial refractory ZRMM and to address said pulse of stimulation or burst of local stimulation pulses after a short duration after the start of the current cycle of the beginning of the ZRMM zone and before the estimated end of said area by storing said duration in previous cycles. 25. Device according to one of claims 2 to 24, wherein the impulse or at least one impulse of a salve of stimulation, falls into said zone (ZRMM), substantially at the location of the myocardium where the occurrence of the said zone (ZRMM). 26. Device according to one of claims 1 to 25 comprising intracavitary pressure measuring means implanted and capable of detect a zone of maximum pressure in the mechanogram plateau cardiac and to which are responsive said means for sending an impulse or a salve of stimulation. 27. Device according to one of claims 1 to 25 comprising at minus an intramyocardial pressure sensing sensor. The device of claim 27, wherein said sensor of myocardial pressure is located in the intra-auricular septum and / or in a free or intraventricular cardiac wall. 29. Device according to one of claims 1 to 25 comprising means for measuring the change in volume of the heart or part of the heart, detecting and storing the interval of the cycle where said volume has reached and maintains its minimum value, said means for addressing an impulse or stimulus burst being responsive to said measuring means. 30. Device according to one of claims 2 to 29 comprising means for detecting oxygen consumption of the heart and / or equivalent, in particular local pH or ketone concentration, and means for detecting the zone of maximum cardiac contraction (ZRMM) by estimation by detecting, during one or more previous cycles, the relative position, in the cycle and / or in the mechanogram, of the impulse or the impulse of a salvo that has generated a post-extrasystolic (EPR) with minimal oxygen consumption by ratio to blood flow measured per minute. 31. Device according to one of claims 2 to 30 comprising:
means for continuously measuring in a location of the heart of ZRE electric refractory zones, means disposed substantially in the region of the heart for accurately measure areas of maximal myocardial contraction ZRMM, the device being arranged to acquire, from said means, the temporal superimposition, in the same cycle, of said zones ZRE and ZRMM and determine the common area, called ZCE critical zone. Apparatus according to claim 31, wherein means for electrical stimulation are arranged to address immediately at least a stimulation pulse in said region of the heart during said area ZCE. Apparatus according to claim 32, wherein said means checking temporal overlap are sensitive to a lag between zones ZRE and ZRMM to address a stimulation pulse or a burst providing at least one pulse within the ZCE zone. Apparatus according to claim 33, wherein said means sensitive ones make it possible to decrease the time interval between two pulses of a salvo to increase the probability of having a pulse during said ZCE zone. 35. Device according to claim 34, characterized in that the duration between two pulses of a salvo can not be reduced to less than one value of the order of 10 ms. 36. Device according to one of claims 31 to 35, wherein, in case of impossibility of sending at least one impulse within the zone ZCE, the device stops the coupled or paired stimulation. 37. Device according to one of claims 2 to 36, wherein memorizes the events and time durations of the ZCE zones during a plurality of cycles and their evolution is analyzed to predict a eventual tendency to remove the ZCE zone and, in this case, to carry out treatment, in particular by infusion of drugs or change in the pace of the STIO in order to affect the duration of the ZRE zones or ZRMM or their overlap. 38. Device according to one of claims 1 to 37 comprising - means for acquiring information relating to the electrocardiogram of a patient, including the heart rhythm, - means for acquiring information relating to the hemodynamic performance of the patient;
analysis means responsive to said acquisition means for simulate the effect of a paired or inotropic coupled stimulation, adapted to the heart of the patient. 39. Device according to claim 38 further comprising means for automatically comparing said information acquired on the hemodynamic performance of the patient to the effect simulated on said performance of an inotropic paired stimulation. 40. Device according to one of claims 38 and 39, wherein said acquisition and comparison means make it possible to acquire and comparison of information cycle by cycle. 41. Device according to one of claims 38 to 40, wherein said means for receiving performance information patient's hemodynamics measure at least one of the following parameters on cardiac contraction:
- slope (dp / dt) of the phases of rise and / or descent of the pressure intracavitary and / or intramyocardial;
duration of the plateau of systolic pressure corresponding to systolic ejection;
- duration of systole (cardiac contraction);

- duration of the diastole (motor active, fast and slow);
- relationship between the durations of diastole and systole;
- quality of the diastole, especially filling depression;
- electromechanical coupling (duration separating the beginning of a complex QRS of the beginning of the mechanical systole it provokes);
- shift between the intramyocardial contraction curve close to the local sensing electrode and the intracavity contraction curve overall. 42. Device according to one of claims 38 to 41, comprising means allowing a comparison of the information relating to the electrocardiogram and the haemodynamic performance of a simulation paired or inotropic coupled stimulation, with information corresponding acquired during a subsequent real inotropic stimulation identical or similar. 43. Device according to one of claims 38 to 42 comprising means to acquire or calculate a threshold level of values of information of simulated hemodynamic performance adapted to the patient, and if the threshold is exceeded, cause a real stimulation, paired or identical inotropic coupling or the like. 44. Device according to one of claims 38 to 43, in which said means for acquiring the information relating to the electro-cardiogram of the patient and the hemodynamic performance of the patient, are arranged to acquire this information at different rates. 45. Device according to claim 44 arranged to impose temporarily in the heart of the patient rhythms varying in stages or gradually, during which the said information is acquired to the electrocardiogram and said performance information corresponding hemodynamics. 46. Device according to any one of claims 38 to 45, in which means responsive to said acquisition means are arranged to simulate the effects of several paired or coupled stimulations inotropic to different heart rhythms. 47. Device according to one of claims 38 to 46 arranged for perform this comparison for a limited number of cycles of the actual inotropic stimulation and, in the event of finding the absence of a level satisfactory hemodynamic performance, terminate stimulation in Classes. 48. The device of claim 47 wherein said number of cycle is of the order of ten or less, including 1, 2 or 3 cycles. 49. Device according to one of claims 47 and 48, arranged for, in case of finding an increase in hemodynamic performance enough, continue the inotropic stimulation and detect and memorize if the initial hemodynamic performance increase is maintained and / or progressively increases for a greater number of cycles. 50. The device of claim 49 wherein said number plus cycles is at least a hundred cycles. 51. Device according to one of claims 38 to 50 wherein said analysis means are arranged to include inotropic effects medications that may interfere with the effect of stimulation inotropic electric. 52. Device according to one of claims 38 to 51 comprising means to emphasize visually and / or quantitatively by calculation, the differences between the curves of the simulation and the actual stimulation corresponding. 53. Use of a device according to one of claims 1 to 52 for the realization of a device for treating heart failure acute or severe. 54. Use of a device according to one of claims 1 to 52 for the preparation of an assembly for the implementation of a method of cardiac regeneration comprising the following steps:
implant in the heart, especially in a right atrium or left and / or right or left ventricle, regeneration cells in particular, in the subendocardial or intramyocardial position, in particular in several groups of cell clusters or in a cellular layer, or mesh cellular, and provide stimulation according to the invention, preferably a paired stimulation. 55. A method of stimulating the heart muscle allowing a significant increase in hemodynamic performance of the heart and / or the treatment of tachycardias comprising the following steps:
- provide a cardiac stimulation device implanted permanently, and, using this device, - automatically acquire the heart rhythm, allowing in particular to know the interval between at least the last two waves R (provoked or spontaneous) of the cardiac cycle which has just ended, - determine in real time, especially on demand, preferably, continually, the duration of the electrical refractory period (ZRE) that follows the last wave R of said cycle, - and address substantially without delay at the end of the said period refractory (ZRE), at least one stimulation pulse. 56. The method of claim 55, wherein means (4) for determining the duration of the electric refractory period (ZRE) sensitive to the detection of that of the pulses of a salvo that has triggered a complex R 'and means for determining the area maximum mechanical refractory ZRMM, and it is determined in said area ZRMM, a zone ZCE posterior to the electric refractory zone ZCE, and if said zone ZCE is existing, one addresses at least one pulse of stimulation in said ZCE zone. 57. Method according to one of claims 55 and 56, including in the case, instead of a burst, the device generates a single pulse of stimulation, in which one acquires, for example, by a scan of a second pulse, the substantially exact duration of the refractory zone, this sweeping being conducted for example during previous cardiac cycles or the current cycle. The method according to one of claims 55 and 56, wherein the start of the stimulus pulse burst is chosen to start, before the estimated end of the refractory period and the duration of this salvo and, by therefore, the number of stimulation pulses is advantageously such that a stimulation pulse will intervene anyway very soon after the end of said refractory period. 59. Method according to one of claims 55 to 58, wherein uses means to advance or recede the occurrence of the salvo by to an estimate of the refractory zone, and / or modify the interval enter the pulses inside the burst, the device presenting means automatic acquisition, in particular by obtaining the intracardiac ECG
to determine, in particular by signal processing electrocardiogram at the detecting electrode and / or stimulating what is the stimulation pulse in the salvo that triggered the wave R ', and thus obtain the electrical refractory zone (ZRE), and, in consequently, possibly modify the salvo. 60. Method according to one of claims 55 to 59, wherein uses means sensitive to spontaneous or stimulated R waves and / or to the determination of the electrical and / or mechanical refractory zones, especially by scanning all the salvo or just inside this salvo and / or means for instant determination of excitability thresholds of the heart, for example by providing intensity stimulation pulses variable, including infra-liminary, to allow their measurement inside a salvo. 61. Method according to one of claims 55 to 60, wherein uses anti-tachycardia pacing and sensitive means to the extrasystoles to automatically stop the programmed stimulation in case of occurrence of excessive hemodynamic instability or severe electrical arrhythmia meeting pre-selected criteria. 62. Method according to one of claims 55 to 61, wherein acquires, in addition, information of cardiac hemodynamics (5,6) accurately measured. 63. The method of claim 62, wherein one or more intracardiac pressure sensors or such sensors arranged to proximity of the heart, and sensors for determining variations in cardiac volume, for example electrical impedance sensors, or ultrasound. 64. Process according to one of claims 62 to 63, in which uses, in addition to the means of acquisition of rhythm, the means of determining refractory zone duration and the means for sending a impulse or salvo, means (7, 10) sensitive to the precise acquisition hemodynamics to determine variations in efficacy of hemodynamics, these means being capable of controlling the sending and possibly the parameters of the pulse or burst, preferably in a way close to the one that produced the hemodynamics, the most favorable for the patient at some point. The method of claim 64, wherein said means act on parameters such as: a programmed ventricular rhythm and / or an automatic adjustment of the beginning or the end or duration of the salvo or the number or characteristics, including width, intensity, polarity, density, pulse interval in the burst, or a localization of sending the salvo to one or between different stimulation electrodes. 66. Process according to one of claims 55 to 65, in which uses means to gradually reduce a salvo to a single impulse, in particular by periodically feeling with at least one second impulse that moves progressively ahead of the impulse stimulating to automatically measure the beginning of the no zone refractory, so that when the exploratory pulse recedes to pulse stimulant, this impulse itself can be pushed back, in particular periodically in the event of instability of operation until the early decline of the precise ventricular pressure / volume curve or increase in oxygen consumption or blood acidosis (pH) or myocardial membrane secretion of electrons, this position which may correspond to the passing of the end of the refractory zone maximum active contraction mechanics (ZRMM). 67. Process according to one of claims 55 to 66, in which acquires metabolic parameters, including consumption of oxygen and / or its equivalents, such as density measurement of myocardial cell membrane electrons, or body augmentation ketones, lactic acid, etc. 68. Method according to one of claims 55 to 67, wherein uses ways to switch from paired stimulation to stimulation coupled, said means being responsive to the acquisition means of electrocardiogram and / or hemodynamics, and / or metabolism myocardial. 69. Method according to one of claims 55 to 68 allowing to treat isolated arrhythmias and extrasystoles, in which one implants a a plurality of electrodes arranged at different locations of the muscle heart and by means of acquisition sensitive to electrical signals appearing on the electrodes, we notice, at an early stage, the occurrence locality of an electrical extrasystole in a myocardial zone, the means to address the stimulation pulses then being rendered sensitive to such a finding to instantly emit in a electrode or in a plurality of electrodes, an impulse or a salve of stimulation whose electrical propagation in the myocardium is directed to the myocardial zone affected by the extrasystole, to cause a fusion complex between the stimulated and extrasystolic depolarizations that blocks the spread of extrasystole. 70. Method according to one of claims 55 to 69 wherein, if quickly detects an extrasystole, decreases or removes, preferably temporarily, the electrical diastolic phases (D), in particular either increasing the pace of stimulation in an electrically controlled heart of the device, either by taking control to address a pulse of stimulation, at the very beginning of the electric diastole. 71. Method according to one of claims 55 to 70 wherein in case appearance of an arrhythmia meeting preselected criteria, increases the number and / or intensity of the burst pulses for enhance the stabilizing effect on myocardial cell membranes, subject to the simultaneous recognition of the maintenance of the tolerance electrical and hemodynamic. 72. Method according to one of claims 55 to 71 in which one uses means allowing in the event of arrhythmias meeting criteria of preselection, and decrease the intensity of the burst pulses, the device monitoring then whether the arrhythmia continues or improves. 73. Inotropic cardiac stimulation method according to one of the Claims 55 to 72, characterized by the following steps:
the electrical signals of the heart are detected, including the premature extrasystoles, at an extracardiac level, preferably epicardial or thoracic, or intracavitary using a plurality detection electrodes implanted in different parts of the heart or to its proximity, - it is determined whether a particular extrasystole is dangerous, by example being early or of ventricular origin, - and instantly sends a train of stimulation to level of at least one stimulation electrode. The method of claim 73, wherein the device has stimulation electrodes in different locations intra or cardiac juxta and one simultaneously stimulates from several or the all of these electrodes to cause fused QRS complexes blocking the non-refractory myocardial spaces before the arrival of the propagation of the extrasystole detected. 75. Process according to one of claims 73 and 74, in which performs sequential recording and memorization of extrasystoles, in particular, extrasystoles considered to be dangerous and, in the case of repetition, preventive stimulation is exercised, particularly by acceleration temporary a basic rhythm of stimulation. 76. Process according to one of claims 55 to 75, in which conducts continuous monitoring of muscle excitability thresholds cardiac card comprising the following steps:
- Inotropic stimulation is done by sending a train pulses so that a pulse of the train occurs very soon after the end of refractory period of heart, the pulse of the pulse train which drives stimulation, - during subsequent cardiac cycles, gradually decrease or suddenly the energy of the stimulating pulse thus detected until level where said train impulse becomes ineffective, therefore sub-preliminary, the resulting pulse of the train then causing the stimulation, and registers the energy of the sub-threshold pulse, thus determining a zone threshold of excitability. 77. The method of claim 76, characterized by the steps following:
- it is verified that the threshold or the threshold area of excitability remains substantially stable, - and we reduce the energy of the pulses of the salvo to a value more low but above the threshold of excitability, by simultaneously checking the regular persistence of stimulated electrical complexes. 78. Process according to one of claims 76 and 77, in which decreases the energy amplitude of the first impulses of a salvo to a below the threshold of excitability, - it is observed whether this decrease provoking an infra-threshold, decreases or not the threshold of myocardial excitability, - and, if this threshold is decreased, the intensity of the pulses is decreased of the salvo, while simultaneously checking for the regular persistence of the stimulated complexes. 79. The method of claim 78, comprising the steps following:
the energy amplitude at which the stimulating pulse is detected, or the train of stimulation or a part of the train, becomes infra-liminal and born generates more observable stimulation, - then we instantly raise the energy amplitude of the pulse become infra-liminary or the part of the pulse train that has become infra-during the next cardiac cycles. 80. The method of claim 79, wherein the energy amplitude of the pulses gradually to determine the new threshold of myocardial excitability in relation to the geometrical shape and the location of the electrodes. 81. Method according to one of claims 55 to 80, wherein address a stimulus pulse or salvo within the zone (ZRMM) located within the plateau of the contraction curve of the mechanogram and during which the contraction of the myocardium is substantially maximum. 82. The method of claim 81, wherein the pulse or minus one pulse of a stimulus burst, falls into said area ZRMM. 83. Process according to one of claims 81 and 82, in which acquires said zone (ZRMM) automatically. 84. The method of claim 83, wherein the intracavity pressure by a sensor and one detects and chooses a zone of maximum pressure in the systolic plateau of the cardiac mechanogram in which the sending of a pulse or a salvo of stimulation. 85. The method of claim 83, wherein the measurement is local intramyocardial pressure near a sensing electrode and stimulation. The method of claim 85, wherein the method is detected.
myocardial pressure in the intra-auricular septum and / or intraventricular. The method of claim 83, wherein the volume variation of the heart, or part of the heart by detecting the area where said volume has reached and maintains its minimum value. 88. Process according to one of claims 81 to 87, in which measures the oxygen consumption of the heart and detects the zone of maximal cardiac contraction (ZRMM) by estimation by detecting at a or several previous cycles, the relative position, in the cycle and / or in the mechanogram, the impulse or impulse of a salvo that has generated a post-extrasystolic reinforcement (PESP) without significant increase in oxygen consumption. 89. Method according to one of claims 55 to 88, wherein - information about the electrocardiogram of a patient is acquired patient, including heart rate, - performance information is acquired hemodynamic patient;
- and we use this information to simulate the effect of stimulation paired or coupled prolonged inotropic. The method of claim 89, wherein, furthermore, compares said acquired performance information hemodynamics of the patient to the simulated effect on said performance of a inotropic paired stimulation. 91. Method according to one of claims 89 and 90, wherein proceeds with the acquisition and comparison of information cycle by cycle. 92. Method according to one of claims 89 to 91, in which measure at least one of the following contraction parameters heart - slope (dp / dt) of the phases of rise and / or descent of the pressure intracavitary or intramyocardial;
- duration of the "plateau" of systolic pressure, corresponding to systolic ejection;
- duration of systole (cardiac contraction);
- duration of the diastole (filling phase);
- relationship between the durations of diastole and systole;
- quality of the diastole, in particular depression of filling or speed and amplitude of the phases fast and slow;
- electromechanical coupling (duration separating the beginning of a complex QRS of the beginning of the mechanical systole it provokes), - shift between the local intramyocardial contraction curve and the global ventricular intracavitary contraction curve. 93. Process according to one of claims 89 to 92, in which compares information about the electrocardiogram and the hemodynamic performance of a paired stimulation simulation or coupled inotropic, with corresponding information acquired during a actual subsequent inotropic stimulation identical or similar. 94. Method according to one of claims 89 to 93, in which acquires or calculates a value threshold level of information from the simulated hemodynamic performance of the patient, and in case of threshold triggers a real stimulation, paired or coupled inotropic identical or similar. 95. Process according to one of claims 89 to 94, in which acquires information about the patient's electrocardiogram and, the performance and hemodynamics of the patient, at different rates, in particular increasing or decreasing in increments or gradually. 96. A method according to any one of claims 89 to 95, in which means sensitive to said arranged acquisition means are used to simulate the effects of several paired or coupled stimulations inotropic to different heart rhythms. 97. Method according to one of claims 89 to 96, in which performs said comparison for a limited number of cycles of the actual inotropic stimulation and, in the event of finding the absence of a level satisfactory hemodynamic performance, we stop the stimulation inotropic in progress. The method of claim 97, wherein said number of cycles is of the order of ten or less, especially 1, 2 or 3 cycles. 99. Method according to one of claims 97 and 98, wherein, in case of finding an increase in hemodynamic performance enough, we continue the inotropic stimulation and detect if the initial hemodynamic performance increase is maintained and / or progressively increases for a greater number of cycles. The method of claim 99, wherein said number plus cycles is at least a hundred cycles. 101. Method according to one of claims 89 to 100, wherein uses the effects of cardiovascular drugs in the analysis previously administered or being administered. 102. Method according to one of claims 39 to 101, wherein emphasizes visually and / or quantitatively, especially by superposition curves, the differences between the simulation curves and stimulation. The method according to one of claims 55 to 102, wherein acquires the cardiac mechanogram, especially until the appearance of a cycle long enough to get a good myocardial contraction, and one then sends a pulse or salve of stimulation at a time inside the mechanogram curve plateau (ZRMM), in particular a little before the end of the electric refractory zone (ZRE) after which stimulates immediately after the end of the electric refractory zone that goes cause a new electrical refractory zone. The method according to one of claims 55 to 103, wherein we have defined a first threshold for increasing the performance hemodynamics / min and / or cardiac contraction, including cardiac output, said threshold being at least 15% or preferably 25%
pre-treatment performance, and adjust the parameters of the stimulation until at least said threshold value is obtained. 105. The method of claim 104, characterized in that, if the increase is not obtained according to said first threshold value at Classes a period of the order of 1 to 10 contractions, the treatment is stopped. 106. A method of treating acute heart failure or severe in which:
- the heart rhythm is automatically acquired, and in particular the interval between at least the last two R waves (caused or spontaneous) of a cardiac cycle that has just ended, - the duration of the period is preferably determined continuously electrical refractory (ZRE) following the last R wave of said cycle, - address substantially immediately, at the end of the refractory period (ZRE), at least one stimulation pulse and, preferably, a salvo stimulation pulses, the duration of the burst then being such that, account given the interval of repetition of the pulses in the burst, an impulse of salvage stimulation is addressed to the heart substantially without delay after the end of the refractory period, and - these steps are repeated during a series of least three contractions if there is a first improvement in the heart performance, - and, in the absence of an improvement, we automatically stop process. The method of claim 106, wherein the comparison is made mechanical performance of the total heart including its blood flow and / or ventricular volume variation, on the one hand, before the implementation of the stages of the process and, secondly, after the implementation of the steps of process, and if the increase in the performance of the heart is greater than 15% is again implemented process steps; 108. Method of cardiac resuscitation in a patient suffering severe or critical heart failure in which:
- the heart rhythm is automatically acquired, and in particular the interval between at least the last two R waves (caused or spontaneous) of a cardiac cycle that has just ended, - the duration of the period is preferably determined continuously electrical refractory (ZRE) following the last R wave of said cycle, - address substantially immediately, at the end of the refractory period (ZRE), at least one stimulation pulse and, preferably, a salvo stimulation pulses, the duration of the burst then being such that, account given the interval of repetition of the pulses in the burst, an impulse of salvage stimulation is addressed to the heart substantially without delay after the end of the refractory period, and - these steps are repeated at least until at least a gradual improvement in cardiac performance detectable. The method according to one of claims 106 to 108, comprising also the steps of the method according to claim 56. 110. Process for the in vitro stimulation of cells intended to be implanted in the heart, said method comprising the following steps:
- obtain and cultivate, in vitro, regeneration cells, preferably in the form of small clusters, or confluent cultures, to be in contact with each other;
- put these confluent cells in electrical conduction contact between them and possibly with the cells of a myocardial tissue previously removed and with an electrical stimulation device, - periodically send electrical pulses to said cells cultivated;
detect the electrical depolarization responses of the cells and / or membrane potentials, and / or electrical refractory zones. The method of claim 110, wherein the stimulation is a simple electrical stimulation at a rate, preferably, of the order normal heart rate, followed after an initial period, by one paired or coupled stimulation according to one of claims 1 to 20, once that clumps or groups of cells in culture are synchronized to manifest an electrical refractory period including a period relatively close to that of the cells of the heart intended to receive the cells. The method according to one of claims 110 and 111, wherein the cells have been modified to overexpress telomerase or protein Sir2. 113. Process for the preparation of living cells, in particular plants, animals and humans, which may be re-established as prophylactic or therapeutic, in which the transport is carried out in a Oocyte, preferably unfertilized or newly fertilized, mammalian homologous or heterologous, preferably preferably completely partially emptied of its nucleus, of a nucleus of a dedifferentiated cell, of to induce a mitotic stage of said transferred nucleus, in that one takes this nucleus during the mitosis and before the end of it, and then introduced this partially dedifferentiated nucleus into mitosis at this stage in a cell, preferably after having removed some or all of the of its nucleus (x), so as to induce and terminate its nuclear division of differentiation and form a cell strain or tissue at a stage of differentiation less advanced than that of said differentiated cell. 114. Process according to one of Claims 110 to 113, characterized in that the transferred nucleus is extracted at the metaphase stage of the first mitosis. 115. Method according to one of claims 110 to 113, characterized in that the transferred nucleus is extracted at the anaphase stage from the first mitosis. 116. Method according to one of claims 110 to 113, characterized in that the transferred core is removed at the prophase stage of the first mitosis. 117. Method according to one of claims 110 to 113, characterized depending on whether the nucleus transferred to the telophase stage is removed from the first mitosis. 118. Method according to one of claims 110 to 117, characterized in that the oocyte is transferred to a myocardial cell nucleus, heart muscle or autorythmic, including sinus cells, Tawara center or beam fibers of His or Purkinje. 119. Process according to claim 118, characterized in that one introduced the nucleus taken before the end of its intra-ovocyte mitosis in a myocardial or muscular cell, preferably emptied from its nucleus or some or all of its nuclei. 120. Method according to one of claims 118 and 119, characterized in that the partially dedifferentiated cells obtained are subjected to preferably after or during their cell multiplication culture after the formation of a confluent set, to periodic electrical stimulation of the cardiac stimulation type, in particular according to one of claims 22 to 24. 121. Process according to claim 120, characterized in that one subjects said cells to coupled or paired electrical stimulation in which this impulse without any contractile effect is addressed soon after the end of the electrical refractory period of cells in culture. 122. Process according to claim 120, characterized in that one subjects said cells to electrical stimulation in cycles comprising a first stimulation pulse and, towards the end of the period refractory, a pulse train, so that at least one of the pulses the train falls shortly after the end of the electrical refractory period of the cell and during their mechanical refractory zone of maximum contraction. 123. The process according to claims 55 to 109, wherein proceed, before the implementation of the steps of the method to an implementation myocardial or muscular cells or the like in the heart, in particular cells obtained by a method according to one of the Claims 100 to 112. 124. Process in which the cells obtained by the method according to one of claims 110 to 123 in the myocardium auricular, especially in the case of a patient suffering from fibrillation Atrial. 125. Method according to one of claims 113 to 117, wherein transfers into the oocyte nuclei, or parts, of follicle cells hair and / or melanocytes for regeneration of hair and / or of its coloring. 126. Segment or arterial stent, especially coronary, aortic, carotid, renal or femoral, including a coated or colonized structure by cells obtained by the process according to one of claims 110 to 122. 127. Physiological arterial segment or stent consisting of cells living, self-contractile and elastic, including autologous, cultivated according to one of claims 110 to 122. 128. Segment or arterial stent according to claim 126 or 127, shaped like an arterial stent arranged to be introduced into a arterial light. The segment or stent of claims 126 to 128, comprising means providing electrical stimulation of the arterial type, coordinated with the ventricular diastole, said cells of the segment. 130. Segment or stent according to one of claims 126 to 129, comprising at least one stimulation and / or detection electrode. The segment or stent of claim 130, wherein the stimulation and / or detection electrode has been introduced into the culture cell to be surrounded by said living cells. 132. Segment or stent according to one of Claims 126 to 131 comprising a sensor, in particular for measuring oxygen saturation and / or metabolic parameters, and an electrocardiographic sensor of detection or stimulation. 133. Segment or stent according to one of claims 126 to 132 comprising a plurality of electrodes arranged to obtain the variations of the local electrical impedance. Arterial segment or stent according to one of claims 126 to 133 having a structure, in particular expandable mesh supporting different cell layers, such as terrarium, myoarterum and periarther, said structure allowing spontaneous growth with progressive enlargement of its light and creation of a vascularization feeding especially the myoarterial part. 135. Segment according to one of Claims 126 to 134, characterized in the structure is made of at least one of the following materials:
PLGA, collagen, globin. 136. Arterial stent without living cells having a structure radially expandable, but rigid enough to maintain the arterial lumen open at least in systole, possibly biodegradable or removable by catheter and capable of receiving a physiological stent according to one of the Claims 126 to 135. 137. Tissue block intended to be implanted in or on the heart and comprising a segment according to one of claims 126 to 135, surrounded of its functional block of peripheral vascular-myocardial tissue provided of arteries, arterioles and capillary and venous network, which can be sewn or anchored in or on the myocardium of the recipient. 138. Biological cardiac pacemaker comprising cells or cardiac autorythmic tissues, partially dedifferentiated, according to one Claims 110 to 122, preferably autologous, homologous, from the recipient organism, and intended to be implanted in the heart or a defective region of the heart.